Subtle neuropsychiatric symptoms of glioblastoma multiforme misdiagnosed as depression

Abstract

Glioblastoma multiforme (GBM) is the most common of the aggressive primary brain tumours arising in adults and has a dire prognosis. Neuropsychiatric symptoms can vary significantly among afflicted persons; psychiatric disturbances may be the predominant presenting symptoms. Distinguishing between functional psychiatric disorders, particularly depression, from other subtle neuropsychiatric disturbances that may accompany GBM can be challenging. The authors present a clinical case and review of the literature in an attempt to highlight the special considerations that should be taken into account when evaluating patients who present with late-onset or atypical symptoms, refractory psychiatric symptoms, or subtle neurological disturbances signalling the need for diagnostic assessment, particularly neuroimaging, for the presence of a tumour. Early diagnosis is critical for improvement in quality of life.

Background

Glioblastoma multiforme (GBM) is the most common of the aggressive primary brain tumours arising in adults and carries a poor prognosis.^{1 2} Patients with brain tumours can manifest predominantly psychiatric symptoms with minimal or no neurological signs,³ as described in the case vignette. Herein, we review the literature addressing the psychiatric manifestations with which patients with GBM present in early phases of the disease and highlight when diagnostic assessments ought to be implemented.

Case presentation

A 46-year-old male patient presented to the psychiatric emergency room due to family’s concern that he was unable to care for himself. For 6 months, he had been treated by an outpatient psychiatrist for depression, but failed two trials of antidepressants (ie, duloxetine and bupropion), with worsening in his adaptive functioning.

Collateral informants revealed that for months he manifested diminished motivation; he became disinterested in customary interests or social engagement. He complained of recurrent headache. He lost 32 pounds over 1½ months and was less active (assumed to reflect reduced appetite and psychomotor retardation of depression, respectively). His stream of thought was slow and, at times, difficult for loved ones to follow. He demonstrated uncharacteristic personality changes such as increased irritability. He was fired from his job after he initiated a conflict with a coworker weeks earlier. Thereafter, he became progressively apathetic and avolitional, that is, remaining in bed for days at a time. For 1 week prior to presentation, he was neglectful of his personal hygiene, for example, failing to bathe or toilet himself, despite being able to move his extremities and ambulate sufficiently. However, he was not described to be tearful or despairing, nor had he manifested preoccupations with guilt, worthlessness or death/dying.

On exam, the patient manifested a restricted affect and seemed emotionless. He manifested circumlocution and word finding deficits. His responses to inquiry were sparse, often delayed and impoverished in content. He was admitted to the hospital with a presumed depression with psychotic features.

Within days of admission, he was noted to be mute and motionless. Although catatonia was entertained among diagnostic possibilities, he still responded to verbal and physical stimuli. Hypokinetic delirium and akinetic mutism were then considered among diagnostic possibilities.

Investigations

Laboratory examination revealed hypernatraemia (151 mmol/L; normal range 133–145 mmol/L) and elevated blood urea nitrogen (41 mg/dL; normal range 6–20 mg/dL), suggesting dehydration. Serum toxicology was non-informative. Complete blood count, metabolic profile and remaining serum electrolytes were unremarkable. He was transferred to a general medical service to manage the presumed dehydration.

Physical examination revealed a reclined, non-verbal man, who did not respond to commands. His vitals were stable. He withdrew from painful stimuli on the left, but not on the right. There was no movement of the right extremities. Pupils were midline, approximately 2 mm, and responded sluggishly to light stimulus. Reflexes were diminished on the right, but were normal on the left. He demonstrated a right-sided extensor response when Babinski reflexes were assessed. MRI revealed a partially necrotic mass measuring approximately 11×6.5×5.4 cm centred within the left frontal lobe with extension through the genu of the corpus callosum into the right frontal lobe (see figure 1). There was a 1.1 cm left-to-right midline shift, with effacement of the left lateral ventricle and downward transtentorial herniation (see figure 1).

Figure 1.

Magnetic resonance images revealing a large left frontal lobe mass with extensive infiltration through the corpus callosum with ventricular effacement.

Outcome and follow-up

Neurosurgical consultation was obtained; because of the extensiveness of the mass, family members elected to pursue palliative care measures only. The patient expired 1 week later. Histological examination at autopsy revealed a pleomorphic astrocytic cell neoplasm predominantly involving the white matter of the left cerebral hemisphere consistent with GBM, along with extensive areas of necrosis.

Discussion

GBM usually presents as a single mass in the cerebral parenchyma, primarily involving the hemispheres and corpus callosum. However, rare cases involving the brainstem and cerebellum have been reported.^4–6

GBM is highly metastatic as it infiltrates adjacent brain regions and can spread via cerebral spinal fluid; the tumour can rapidly increase in size over the course of a brief time, for example, in as little as a few days or weeks.⁷ Tumour location may influence progression and metastasis. Tumour lateralised to a hemisphere will likely spread to adjacent regions. By contrast, GBM involving the corpus callosum, referred to as ‘butterfly glioma’, often metastasises to the temporal and occipital lobes bilaterally.^{2 6} Hence, the progression of symptoms and patient survival time are often correlated to the rate of tumour growth/expansion.^{7 8}

Although symptom manifestation is likely to be determined by the location and size of the tumour, GBM often becomes quite large before prominent neurological symptoms are detected. The evolution of a patient’s symptoms is likely to be impacted by tumor-induced increases in intracranial pressure; functional disruptions in the transmission of, and connections between, neural pathways produced by compression of grey and/or white matter; and/or cerebral ischaemia produced by vascular compression.⁹

Psychiatric and neurological manifestations of GBM

A review of the literature was conducted to gather reports of GBM and psychiatric symptoms from 1950 to 2019 using MEDLINE, PubMed, Ovid, Psych Info and MedScape. Search terms included GBM combined with each of the following terms: psychiatric disorders, psychiatric symptoms, depression, mania and psychosis. Case reports were included if psychiatric manifestations of GBM were described. Articles were excluded if they failed to report neuropsychiatric manifestations with which patients afflicted with GBM presented or if the articles focused solely on treatment. The literature search yielded 25 case reports and case series; no cross-sectional studies were retrieved. From these, 26 cases of patients with glioblastoma (excluding other types of brain tumours) were discovered, summarised in table 1. The table summarises the locations of the tumour, the primary psychiatric disorder(s) for which psychiatric treatment was sought, and associated neurological symptoms.

Table 1.

Glioblastoma multiforme tumour location: neurological and psychiatric manifestations

Tumour location	Psychiatric symptoms	Neurological symptoms	Gender/age	Reference #
Left frontal lobe	Postpartum depression	Bilateral headache; mild disorientation; severe deficits in long term memory	F/28	10
Left frontal lobe	Depression; auditory hallucinations	Hyperreflexia; facial droop	F/60	22
Right frontal lobe	Depression	Delirium	M/34	23
Right frontal lobe	Schizophrenia; new-onset catatonia	Headache	M/47	11
Right frontal lobe	Pathological laughter	Left hemiparesis	F/60	24
Right frontal lobe, extending to corpus callosum	Worsening anxiety; insomnia	Progressive left sided weakness; speech deficits	F/53	34
Bilateral frontal lobes	Mood and anxiety symptoms, PTSD	Headache; aphasia; left sided numbness	M/39	12
Bilateral frontal lobes	Depression, negativism, mutism	None initially; subsequent hyperreflexia, nuchal rigidity	F/52	25
Left fronto-parietal lobes	Major depression, agoraphobia with panic attacks	Later-onset right-sided weakness	F/55	13
Left fronto-temporal lobes, extending to right frontal	Treatment-resistant depression, anhedonia, suicidal ideas	History of seizures	M/53	14
Temporal lobe	Depression and catatonia (echolalia)	Apraxia; gait disturbance; urinary incontinence	M/57	30
Temporal lobe	Complex visual hallucinations	Visual field defect (left superior quadrantanopia)	M/44	26
Left temporal lobe	History of schizoaffective disorder; developed new persecutory beliefs	Left temporal headache	F/38	15
Right temporal lobe	New-onset mania with psychotic features	Right papilledema, wide based gait; mild left sided hemiparesis.	M/60	27
Left temporo-parietal lobes	Depression	Occipital headache; disorientation; weakness; unsteady gait	M/40	16
Right temporo-parietal lobes	Depression; apathy	Forgetfulness; ideomotor apraxia; construction apraxia; poor planning and self-monitoring on draw-a-clock test	M/65	20
Right temporal lobe and hippocampus	Depression	Spells of ‘musical sounds’; eventual lethargy, left hemiplegia	M/53	17
Right parietal lobe	History of depression; developed manic-like state	Headache, plantar responses were extensor; left hemiparesis; visual field deficits	F/65	18
Left thalamic	History of PTSD; developed depression	Memory difficulties; headache	F/24	3
Corpus callosum	Depression; new-onset psychosis	Ataxic gait	M/59	28
Splenium of corpus callosum	Depression and Cotard’s syndrome	Progressive right leg paresis; ataxia; abulia	M/60	32
Posterior corpus callosum	Depression	Visual memory deficits	F/46	21
Third ventricle	Depression	Polydipsia; polyuria	F/29	33
Right hippocampus	Anxiety	Headache; left sided weakness	F/40	17
Limbic structures	History of depression; acutely developed mania	None specified	F/56	31
Medulla	Hysteria; conversion symptoms	Foot numbness; horizontal nystagmus; progression to left sided weakness; cerebellar ataxia; right extensor plantar response	F/31	29

Neurological symptoms

Neurobehavioural symptoms can vary significantly among patients afflicted with GBM. Due to the effects of increased intracranial pressure, brain neoplasm classically presents with generalised symptoms, that is, headache, vomiting and seizure.^{3 10–18} Fast-growing tumours, particularly within the frontal lobe and corpus callosum^{3 19} can produce cognitive changes3 10 12 16 20 21 and/or neurological signs12 13 17 18 22–29 but these may not be appreciable until the tumour becomes quite large. Subtle and atypical neuropsychiatric symptoms may predominate early in the course of tumour growth/expansion.

Psychiatric symptoms

The emergence of psychiatric symptoms may be the initial, and often insidious, sign of an evolving GBM. In several of the cases summarised here, it was the psychiatric symptoms that prompted clinical presentation.3 10 13 14 16 17 20–23 26–28 30 31 Psychiatric manifestations related to GBM in the cases retrieved here have been reported in adults whose ages spanned 24–65 years; most (62%) of the afflicted persons were middle-aged.

Depression was the primary psychiatric symptom manifestation of the underlying GBM in 62% (16/26) of retrieved cases.3 10 13 14 16–18 20–23 25 28 30 32 33 Other mood disturbances reported among GBM patients included pseudobulbar affect-like states,²⁴ manic-like states^{27 31} and anxiety,3 12 13 17 34 some of the latter of which co-occurred in depressed patients. Mood disorders were associated with tumours involving the frontal lobes,10 12–14 22–25 34 temporal lobes14 16 17 20 30 and limbic structures.^{17 31} Patients manifested psychotic symptoms in 35% (9/26) of cases.11 15 22 25–28 30 32 Psychotic symptoms tended to be predominantly associated with tumours localised in the temporal lobes,15 26 27 30 31 although some of the cases reported here also traced the emergence of psychotic symptoms to tumours predominantly effecting the frontal lobes^{11 22 25} and corpus callosum.^{28 32} There was a paucity of GBM cases involving the parietal lobe and none involving the occipital lobes; it has been argued that such tumours tend to be relatively ‘silent’ with regard to psychiatric manifestations.17 31 35 36

Although psychiatric symptoms may be the initial clue to the presence of GBM, there is no clinical method of localising a brain tumour by its psychiatric manifestations.^{16 37} The descriptions of psychiatric symptoms and the criteria underlying the reported psychiatric diagnoses may not have been uniform in most of these reports, limiting the extent to which conclusions can be derived regarding clinical–anatomic relationships. Further, in contrast to what is typically encountered with cerebrovascular lesions, neoplasms may not be confined to discrete brain areas. Infiltrating tumours, and GBM in particular, can be associated with oedema, mass effects, hydrocephalus and vascular compromise, which together produce diverse clinical effects that impede the ability to precisely correlate neurobehavioural symptoms with tumour location.31 35 38 39

In seven cases, the patient had no history of psychiatric illness and the psychiatric symptoms arose de novo.10 22 24–27 30 In some of these, psychiatric disorders emerged in patients beyond the expected age ranges in which such disorders would typically arise,22 24 25 27 30 and signalled the need for further diagnostic assessments.

For patients with pre-existing psychiatric disturbances, it becomes difficult to determine whether there was a causal/functional relationship between the glioblastoma and the psychiatric disorder. For example, in some of these cases, the patient had a history of psychiatric illness for years before the discovery of the GBM.3 11 15 31 34 It is plausible that the tumour coincidentally emerged in the patient who happened to have a psychiatric illness, but that the tumour and psychiatric illness were causally independent. In only a few cases was it possible to establish some support for a causal association when symptoms resolved following after tumour resection.10 13 24 30 In other cases, the evolution of new or unusual psychiatric symptoms3 11 13 16 21 26 28 30 32 33; poor response to treatment in a person who had previously responded favourably to psychiatric treatment^{14 25}; or the emergence of new cognitive and neurological symptoms11 12 15 17 18 20 23 29 34 provided clues to the presence of the tumour. For example, in one well described case,³ a patient with a 4-year history of mood disturbance had a series of multiple brain images undertaken during the course of her psychiatric illness. Only once she began to develop more refractory psychiatric symptoms (less responsive to treatment) and some neurological signs did imaging reveal significant findings.

Impediments to identifying GBM based on psychiatric symptoms

In some cases, as with the case presented here, diagnosis of GBM was delayed because of the tendency to make misattributions as to the origins of the neuropsychological symptoms with which patients presented.¹⁵ For example, psychiatric/psychological assessments were unduly influenced by the patient’s premorbid history, for example, one patient’s symptoms of disorientation and fluctuation of consciousness were attributed to alcohol withdrawal and then subsequently, to Wernicke’s encephalopathy, because he had a long history of alcohol use disorder.²³ In other cases, unusual psychiatric symptoms were ascribed to psychosocial stressors^{16 27 29}; to co-occurring disorders (ie, to PTSD) because the patient had recently been in a motor vehicle accident¹²; and even to conversion reaction^{13 29} because of the patient’s unusual neurological symptoms. It was only when attention was paid to the neuropsychological symptoms, or their worsening, that further investigation into a possible brain tumour was undertaken, and the GBM was diagnosed. Although earlier diagnosis may not have altered the clinical outcomes for many of the cases summarised here, it may have allowed the patient, and their families, to optimise treatment and/or palliative interventions.

Clinical features distinguishing GBM from functional psychiatric disorders

Patients afflicted with brain tumours, even in the absence of overt neurological signs/deficits, display neurocognitive impairments in various domains. Particularly in the early stages of the disease, neurocognitive impairment tends to be subtle and may therefore remain under recognised or even misattributed to a psychiatric disorder. In the absence of formal neuropsychological assessment, such symptoms may escape clinical attention because the subtlety of symptoms evades caregiver attention and lack of patient self-awareness prevents reporting of symptoms.⁴⁰

Differentiating psychiatric disorders, particularly depression, from subtle neuropsychological disturbances accompanying GBM can present significant challenges. In the present case, his family members and outpatient treatment provider assumed he was manifesting symptoms of worsening depression. GBM was unveiled only after his symptoms progressed to the point of akinetic mutism, prompting further investigation. One of the more common dilemmas involves distinguishing neurologically based motivational deficits from depression. Disorders of diminished motivation (DDM) are specific neuropsychiatric syndromes thought to arise from disruptions in the dopaminergic networks within the frontal lobes, basal ganglia, thalamus, substantia nigra and mesolimbic structures,^41–44 and are characterised by a continuum of impairments in goal-directed behaviours. In its mildest form, such impairments encompass apathy, with features of reduced motivation and self-initiated behaviour.⁴⁵ Abulia is regarded as a more severe expression of apathy, characterised by reduced movement and a lack of spontaneous speech.⁴¹ In its most severe form, akinetic mutism is characterised by marked reduction of most motor functions, bradykinesia, monosyllabic speech and diminished facial expression.^45–48 Individuals with akinetic mutism can orient toward an auditory stimulus, are alert, and can move (although in a delayed and slowed fashion) to repeated commands. Because features of DDM resemble the psychomotor retardation of depression, caregivers often mistakenly construe DDM as a depressive state. Clinically, DDM can be distinguished by the lack of sadness, irritability, negative thoughts (despair, guilt or death preoccupations and somatic concerns) and vegetative symptoms of depression.^{49 50}

Diagnostic approaches

Given the varied and sometimes perplexing psychiatric presentations of patients with GBM, the importance of careful history gathering and neurological examination cannot be overstated. Finding an unusual array of psychiatric, cognitive and/or neurological symptoms that do not conform to the features expected in functional psychiatric and neurological disorders should prompt further investigation. Neuropsychological testing may identify and clarify the extent of cognitive deficits too subtle for detection on mental status screening assessments, and thereby clarify whether further diagnostic assessment is warranted.

Clinicians might consider employing multi-dimensional assessments to assess neuropsychiatric symptoms, for example, the Neuropsychiatric Inventory.^{51 52} Although developed and customarily employed to measure neuropsychiatric functioning of patients with neurocognitive disorders, this caregiver based instrument addresses multiple domains of functioning, including apathy and depression, which may help clinicians distinguish between these two conditions. The utility of such instruments in patients with brain tumours has not been empirically established, however.

Controversy attends the utility of neuroimaging for patients presenting with predominantly psychiatric symptoms, particularly in those for whom neurological examination is unrevealing.^{53 54} In one series, brain imaging was undertaken in 337 patients admitted to an inpatient psychiatric facility. In only four (1.6%) cases (two of whom had a previously unsuspected brain tumour) was neuroimaging able to unveil abnormalities in those who did not have a known history of neurological disorder or for whom examination was neurologically ‘silent’.⁵⁵

Clear guidelines are lacking to inform when such neuroimaging should be undertaken.^{31 55} Neuroimaging is indicated in patients presenting with neurological signs, confusion, cognitive impairments, headache and so on. It should also be considered for those with late-onset and/or atypical psychiatric symptoms, an acute change in relative to one’s previous symptoms, negative family history of psychiatric disturbance and symptoms refractory to treatment.^{16 56 57}

Learning points.

• Glioblastoma multiforme (GBM) has a dire prognosis, partly due to its aggressive nature and the likelihood that diagnosis is often delayed, especially in its early stages, due to non-specific symptomology.

• GBM can present with a variety of neurological, cognitive and psychiatric symptoms. Infrequently, psychiatric manifestations are the only presenting symptoms of a brain tumour.

• The case presented here illustrates that symptoms of personality changes and, in particular, disorders of motivation, may signal a neuropsychiatric impairment. Although features of disorders of diminished motivation may overlap considerably with those encountered in depression, the absence of sadness, guilt, worthlessness or death/dying likely signalled that this was something other than a depressive disorder.

• Careful history taking and physical examination may point to subtle deficits that may warrant further investigation, that is, neuropsychological assessment and neuroimaging.