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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatr. Sep 22, 2015; 5(3): 273-285
Published online Sep 22, 2015. doi: 10.5498/wjp.v5.i3.273
Psychiatric aspects of brain tumors: A review
Subramoniam Madhusoodanan, Mark Bryan Ting, Tara Farah, Umran Ugur
Subramoniam Madhusoodanan, Department of Psychiatry, St. John’s Episcopal Hospital, Far Rockaway, NY 11691, United States
Subramoniam Madhusoodanan, Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY 11203, United States
Mark Bryan Ting, Community Behavioral Health Center, Fresno, CA 93720, United States
Mark Bryan Ting, Bio-Behavioral Medical Clinics, Fresno, CA 93711, United States
Tara Farah, Medical Student IV, Medical University of Lublin, 20-059 Lublin, Poland
Umran Ugur, Medical Student IV, Ross University School of Medicine, Miramar, FL 33027, United States
Author contributions: All authors contributed to this paper.
Conflict-of-interest statement: The authors report no financial or other conflicts of interest in connection with this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Subramoniam Madhusoodanan, MD, Associate Chair, Department of Psychiatry, St. John’s Episcopal Hospital, 327 Beach 19th Street, Far Rockaway, NY 11691, United States. sdanan@ehs.org
Telephone: +1-718-8697248 Fax: +1-718-8698532
Received: May 6, 2015
Peer-review started: May 8, 2015
First decision: July 10, 2015
Revised: August 15, 2015
Accepted: September 7, 2015
Article in press: September 8, 2015
Published online: September 22, 2015

Abstract

Infrequently, psychiatric symptoms may be the only manifestation of brain tumors. They may present with mood symptoms, psychosis, memory problems, personality changes, anxiety, or anorexia. Symptoms may be misleading, complicating the clinical picture. A comprehensive review of the literature was conducted regarding reports of brain tumors and psychiatric symptoms from 1956-2014. Search engines used include PubMed, Ovid, Psych Info, MEDLINE, and MedScape. Search terms included psychiatric manifestations/symptoms, brain tumors/neoplasms. Our literature search yielded case reports, case studies, and case series. There are no double blind studies except for post-diagnosis/-surgery studies. Early diagnosis is critical for improved quality of life. Symptoms that suggest work-up with neuroimaging include: new-onset psychosis, mood/memory symptoms, occurrence of new or atypical symptoms, personality changes, and anorexia without body dysmorphic symptoms. This article reviews the existing literature regarding the diagnosis and management of this clinically complex condition.

Key Words: Brain tumors, Psychiatric symptoms, Neuropsychiatric, Behavioral symptoms, Diagnosis, Management, Neuroimaging

Core tip: Psychiatric symptoms may rarely be the only presentation of a brain tumor. Any type of psychiatric symptoms can occur with brain tumors. Unfortunately, the symptoms generally do not have any localizing value. New onset psychosis, mood or memory symptoms, occurrence of new or atypical symptoms, personality changes and anorexia without body dysmorphic symptoms, suggest a work up including neuroimaging. Early diagnosis is critical for improved quality of life for the patient.



INTRODUCTION

The majority of large studies discussing brain neoplasms and psychiatric symptoms date back to the 1930’s[1]. Since psychiatric nomenclature and disease parameters change constantly, it is difficult to analyze this topic in a consistent manner.

Brain tumors are relatively common with an annual incidence of 9 per 100000 for primary brain tumors and 8.3 per 100000 for metastatic brain tumors. Brain tumors may be classified based on their histopathologic characteristics or anatomical location. There are two types of tumors: ones that are primary, originating from the brain tissue, and ones that metastasize to numerous locations throughout the brain. Because of this, metastatic tumors often present with more neuropsychiatric symptoms. The most common primary brain tumors are gliomas, which are divided into several types: astrocytomas, oligodendrogliomas, and ependymomas. The groups of brain tumors that are not from the glial tissue include meningiomas, schwannomas, craniopharyngiomas, germ cell tumors, pituitary adenomas, and pineal region tumors. Majority of all brain tumors are gliomas, accounting for 40%-55%. Tumors metastasizing to the brain account for 15%-25% of all brain tumors[2].

Most brain tumors present with specific neurologic signs due to mass effect. However, in rare cases they may present primarily with psychiatric symptoms. A study by Keschner et al[3] reported that 78% of 530 patients with brain tumors had psychiatric symptoms. However, 18% of the 530 presented only with these symptoms as the first clinical manifestation of a brain tumor. Due to the neuronal connections of the brain, a lesion in one region may manifest a multitude of symptoms depending on the function of the underlying neuronal foci. Symptoms of brain lesions depend on the functions of the networks underlying the affected areas[1]. For instance, a significant association has been found between anorexia symptoms and hypothalamic tumors, a probable association between psychotic symptoms and pituitary tumors, memory symptoms and thalamic tumors, and mood symptoms and frontal tumors[4].

Management of brain tumors consists of surgical resection of the tumor, stereotactic radiosurgery, radiotherapy, and chemotherapy. Treatment of the psychiatric symptoms caused by brain tumors depends on the presenting symptoms and includes antidepressants, antipsychotics, mood stabilizers, and anxiolytics[1].

Although there may be an association between some tumor locations and psychiatric symptoms, it is difficult to predict the symptoms based on the location or vice versa. This paper will explore the diverse manifestations, diagnosis, and management of brain tumors that present primarily with psychiatric symptoms.

LITERATURE REVIEW

A comprehensive review of the literature was conducted regarding reports of brain tumors and psychiatric symptoms from 1956-2014. Search engines used include PubMed, Ovid, Psych Info, MEDLINE, and MedScape. Search terms included psychiatric manifestations/symptoms, brain tumors/neoplasms. Our literature search yielded case reports, case studies, and case series. There are no double blind studies except for post-diagnosis/-surgery studies.

We found 172 cases with psychiatric symptoms. Psychiatric symptoms were assigned to 7 main categories: depressive symptoms, apathy, manic symptoms, psychosis, personality changes, eating disorders, and a miscellaneous category for the less frequently encountered symptoms. Each category will be discussed. Some reports may be included in more than one category due to combination of symptoms.

Depression (Table 1)
Table 1 Brain tumors and depressive symptoms[41].
Ref.Psychiatric symptomsTumor locationTumor typeRemarks
Zivković et al[42], 2014Depression, impairment in memory, motivation, concentration, insomnia, increased appetite, headachesParietal lobeEpidermoid tumorSubsequent neurological symptoms led to CT scan and diagnosis of the brain tumor
Assefa et al[43], 2012Depression, anxiety, insomnia, headache, nausea, vomiting, unilateral abducens palsyParasellar and retrosellar areas of the petrous apex, temporal lobeMeningiomaNeurologic deficit with psychiatric symptoms
Ozdilek et al[44], 2011Depression, anxiety, headacheLeft temporal lobeGlial tumorPersistent headache led to neurologic consult and CT, and diagnosis
Cheema et al[45], 2010Depression, anhedonia, low energy, insomnia, suicidal ideationsLeft frontal and temporal lobeGlioblastoma multiformeDuration of psychiatric symptoms of 10 yr make the association of glioblastoma questionable and possibly unrelated
Bunevicius et al[46], 2008Depression, Parkinsonian symptomsRight fronto-temporalMeningiomaSubsequent neurological symptoms led to CT scan and diagnosis of the brain tumor
Bunevicius et al[46], 2008Depression, psychosisLeft temporal lobeIntra-cerebral cystRefractory symptoms
Habermeyer et al[47], 2008Depression, deliriumRight frontal lobeGlioblastoma multiformePsychiatric and neurological symptoms at initial presentation
Oreskovic et al[48], 2007Depression, attention deficit hyperactivity disorderSuprasellar and pineal regionsGerm cell tumorGood prognosis with chemotherapy and radiation
Moise et al[49], 2006Depression, headache, memory lossRight thalamusGlioblastoma multiformePartial improvement of symptoms with surgical treatment and antidepressants
Madhusoodanan et al[50], 2004Recent depressive symptoms, anger and agitationLeft parietalHigh grade glial neoplasm with sporadic cellsResolution of depressive symptoms after surgery, chemo- and radiation therapy
Kohler et al[32], 2001Depressive symptoms refractory to antidepressants, following surgical resection of left frontal neurocytomaLeft lateral ventricle, left frontal encephalomalaciaNeurocytomaGood response to ECT
Ghaziuddin et al[31], 1999Depressed mood, mania, suicidal ideation, irritability, guilt, grandiosity, early insomnia, olfactory hallucinationsBrainstem (ponto-mesencephalic)AstrocytomaImprovement with ECT
Kaplan[51], 1997Progressive depression and anxietyRight frontal and parietalUnknown
Kugaya et al[52], 1996Depressed mood, agitation, depersonalization, ideas of reference, suicidal ideationEpendymalCystPartial removal of cyst led to complete resolution of symptoms
Griffith[53], 1995DepressionOlfactory areaEsthesioneuroblastoma
Filley et al[8], 1995Severe depression, extensive weight lossLeft frontalSquamous cell carcinoma
Chipkevitch et al[54], 1993Atypical anorexia nervosa, depressionHypothalamusTeratoma
Fulton et al[55], 1992Reduced communication, depression, seizures, neurologic signsRight frontal lobeAstrocytomaPoor response to steroid treatment
Goodman et al[56], 1992Late-onset depressive symptoms, left-sided Horner’s syndromeSeveral bi-frontal massesUnknown
Ko et al[57], 1989Depressive symptoms, emotional lability, amnesia for recent eventsMultiple metastatic left fronto-parietal lesionsOrigin in right lungNo surgical intervention
Tanaghow et al[58], 1989Depressed mood, social withdrawal, personal neglect, apathyAnterior corpus callosumUnknown
Upadhyaya et al[59], 1988Depression and delusionsThird ventricleColloid cyst
Greenberg et al[29], 1988Treatment-resistant depression with delusionsLeft fronto-parietalMeningiomaGood response of psychiatric symptoms to ECT
Goldstein et al[30], 1988DepressionRight frontalMeningiomaGood response to ECT
Summerfield[60], 1987Depression, psychosomatic symptomsCerebellumHemangioblastoma
Ghadirian et al[61], 1986Depression and anxiety followed by visual hallucinationsRight temporal lobeMeningioma
Uribe[62], 1986Depressive symptoms with rage episodes, forgetfulness, disturbance in short-term memory and abstract thinking, later-onset headaches, disorientation, gait unsteadiness, hemiparesisLeft temporo-parietalGlioblastoma multiforme
Dietch[63], 1984Agoraphobia with panic attacks and major depression; later-onset right-sided weaknessLeft fronto-parietalGlioblastoma multiformeGood response to imipramine, resolution of symptoms after surgery
Maurice-Williams et al[64], 1984Depression, focal seizuresFrontalMeningiomaImprovement of symptoms after tumor was removed
Fisher et al[65], 1983DepressionLimbic systemCNS lymphoma
Barbizet et al[66], 1982Rage attacks, Bulimia, uninhibited and brutal sexual behavior, periods of depression with suicide attemptsFronto-temporalAstrocytoma
Lahmeyer[67], 1982Depression and urinary incontinenceBilateral frontalMeningiomaGood response to amphetamines
Littman et al[68], 1981Depression, speech difficultiesLeft temporalUnknown
Khuan et al[69], 1979Depression, poor work performanceRight thalamusUnknown
Burkle et al[70], 1978Depression, hypersomnia, anhedonia, low energy, poor concentration, memory lapsesThird ventricle with obstruction of lateral ventriclesColloid cyst
Carlson[71], 1977Severe depression; prior history of seizuresFrontalMeningiomaComplete resolution of symptoms after surgery
Carlson[71], 1977Severe depressionRight frontalGrade IV astrocytomaResolution of symptoms after surgery
Scherrer et al[72], 1974Depression followed by euphoria, then seizuresFrontalUnknown
Blustein et al[73], 1972DepressionRight temporalGrade I astrocytoma
Avery[74], 1971Depression, apathyRight cribriform plateMeningiomaPost-op manic episode before resolution of symptoms
Avery[74], 1971Depression, apathyRight cribriform plateMeningiomaImprovement after surgery

Depression may be seen in different stages (before, during or after diagnosis/treatment) of brain tumors. Depression was reported in 2.5%-15.4% of primary brain tumors[5]. According to Mainio et al[6], depression was found in 44% of all brain tumor patients, primary and metastatic, and was associated with functional impairment, cognitive dysfunction, reduced quality of life, and reduced survival[7]. It was also noted that depression was more commonly found in frontal lobe tumors[8-10]. More specifically left frontal lobe tumors were more frequently associated with depression and akinesia[11].

Apathy (Table 2)
Table 2 Brain tumors and apathy[41].
Ref.Psychiatric symptomsTumor locationTumor typeRemarks
Aydin et al[75], 2013Loss of self-generated behavior, irritability, disinhibition, impulsivityMidline subfrontal regionMeningiomaPsychiatric and neurologic symptoms with consequent diagnosis of brain tumor
Filley et al[8], 1995Apathy, social-withdrawal, poor self-careBifrontalBenign meningioma
Filley et al[8], 1995Apathy, irritability, anomia, right hemiparesisLeft frontal lobe and genu of corpus callosumImmunoblastic lymphoma
Filley et al[8], 1995Apathy, amnesia, poor affectThalamic and fornical columnsGonadotropic cell pituitary adenoma
Fulton et al[55], 1992Loss of interest, poor concentration, withdrawal, lack of communication, neurologic signsLeft frontal lobe involving corpus callosumUnknown
Tanaghow et al[58], 1989Depressed mood, social withdrawal, personal neglect, apathyAnterior corpus callosumUnknown
Burkle et al[70], 1978Depression, hypersomnia, anhedonia, low energy, poor concentration, memory lapsesThird ventricle with obstruction of lateral ventriclesColloid cyst
Avery[74], 1971Euphoria, drowsiness, and apathyTuberculum sellaeMeningiomaSome residual psychiatric disturbance following resection
Avery[74], 1971Depression, apathyRight cribriform plateMeningiomaPost-op manic episode before resolution of symptoms
Avery[74], 1971Depression, apathyRight cribriform plateMeningiomaImprovement after surgery
Avery[74], 1971Apathy, change in work behaviorCribriform plateMeningiomaImprovement after surgery

Apathy must be distinguished from major depressive disorder and chronic fatigue syndrome. Patients presenting with apathy when asked about their mood, state that they are not depressed, but instead have chronic fatigue and lack of motivation[12]. This may be associated with a functional disconnection between the frontal lobe and paralimbic areas, or damage in these areas[13,14]. Levy et al[15] suggests that apathy is common in neurodegenerative disorders and is independent of depression. The diagnostic criteria for apathy suggested by Starkstein et al[16] include lack of motivation, diminished goal-directed behavior (lack of effort, or dependency on others to structure activity), diminished goal-directed cognition (lack of interest in learning new things or in new experiences, or lack of concern about one’s personal problems), or diminished emotions (unchanging affect, or lack of emotional responsivity to positive or negative events).

Manic symptoms (Table 3)
Table 3 Brain tumors and manic symptoms[41].
Ref.Psychiatric symptomsTumor locationTumor typeRemarks
Bhatia et al[76], 2013Visual hallucinations, grandiosity, excessive talking, elated moodThird ventricleNeuroepithelial cystPsychiatric symptoms and diagnosis of brain tumor with no development of neurologic symptoms
Yetimalar et al[77], 2007Personality change, psychomotor agitation, enhanced talkativeness and sex drive, decreased need for sleepPonsCavernous angiomaNeurologic symptoms developed after the brain tumor was diagnosed
Ghaziuddin et al[31], 1999Depressed mood, mania, suicidal ideation, irritability, guilt, grandiosity, early insomnia, olfactory hallucinationsBrainstem (ponto-mesencephalic)AstrocytomaImprovement with ECT
Mazure et al[78], 1999Late-onset manic episode with psychotic features; no neurologic signsRight temporal lobeGlioblastoma multiformeGood and rapid response of psychiatric symptoms to perphenazine
Filley et al[8], 1995New-onset manic symptomsBitemporalGlioblastoma multiforme
Mark et al[79], 1991Treatment-resistant bipolar disorderAcoustic nerveNeurinomaSymptoms resolved completely after tumor resection
Greenberg et al[29], 1988Manic symptomsBrainstemMetastases, origin unknown
Jamieson et al[17], 1979ManiaRight occipital, temporal and parietal lobesMetastatic tumors- unknown primary source
Scherrer et al[72], 1974Recurrent manic episodesFrontalUnknown
Avery[74], 1971Mania, euphoriaOlfactory nerveMeningiomaSome residual psychiatric disturbance following resection

In addition to depression, patients with brain tumors can also present with other mood symptoms, such as mania. There are reports which show that while depression was associated with left frontal tumors, mania was found more commonly with right frontal tumors presenting with characteristics such as euphoria and underestimation of the significance of their illness[11]. Right hemisphere lesions have been reported to present as manic symptoms[17-19].

Psychosis (Table 4)
Table 4 Brain tumors and psychotic symptoms[41].
Ref.Psychiatric symptomsTumor locationTumor typeRemarks
Krayem et al[27], 2014Psychosis, auditory hallucinations, self-injurious behaviorRight temporal lobeAstrocytomaPsychosis developed either from tumor recurrence or right temporal brain tissue loss post-surgery
Kaloshi et al[80], 2013Visual and auditory hallucinations, spasmodic laughter, minimal spontaneous speechCerebellumGlioneuronalPartial improvement of symptoms with surgery
Arasappa et al[81], 2013Lethargy, anhedonia, persecutory delusions, and third person auditory hallucinationsFourth ventricleChoroid plexus papillomaImprovement with surgery
Canuet et al[26], 2011Schizophrenia-like psychosisRight parietal lobeMeningiomaPsychosis developed 6 yr after initial surgery with tumor recurrence. Gradual improvement with antipsychotics
Bunevicius et al[46], 2008SchizophreniaLeft temporal lobeAnaplastic oligodendrogliomaImprovement with surgery
Bunevicius et al[46], 2008Depression, psychosisLeft temporal lobeIntra-cerebral cystRefractory symptoms
Bunevicius et al[46], 2008SchizophreniaLeft temporal lobeGlioblastoma multiforme
Parisis et al[82], 2003Peduncular hallucinosis (complex visual hallucinations), sleep impairmentCerebellar metastasesMetastasesMechanism thought to be extrinsic compression of posterior midbrain-pons by mass edema
Rueda-Lara et al[83], 2003Delusions, hallucinationsPituitaryHormone producing adenoma
Maiuri et al[84], 2002HallucinationsPosterior thalamusGlioblastoma multiformePartial improvement of symptoms with surgical treatment and antidepressants
Miyazawa et al[85], 2001Headaches and psychotic symptomsPinealPineal meningiomaImprovement with surgery
Miyazawa et al[85], 2001Headaches and psychotic symptomsPituitaryUnknownImprovement with steroid/hormone treatment
Craven[86], 2001Acute psychotic episodePinealGerminoma
Vardar et al[87], 2000Psychotic symptoms and cognitive deteriorationRight temporo-parietalArachnoid cyst
Mordecai et al[88], 2000Psychotic and obsessive-compulsive symptoms, left-sided weakness, diabetes insipidus, decline in academic functioningBilateral basal gangliaGerminoma
Werring et al[89], 1999Visual hallucinations, palinopsia, posterior headacheOccipitalTuberculoma
Carson et al[90], 1997Pediatric psychosis - hallucinations, aggression, violenceThird ventricleChoroid plexus papillomaSymptoms improved after surgical removal
Ball[91], 1996Persecutory delusions, auditory and visual hallucinations, fluctuating levels of consciousness followed by grand-mal seizuresCerebellopontine angleMeningioma
Filley et al[8], 1995Psychotic symptoms (perceptual disturbances)TemporalLow-grade oligoastrocytoma
Okada et al[92], 1992Positive and negative psychotic symptomsLeft basal gangliaUnknownPositive symptoms resolved after surgical resection, but negative symptoms persisted
Trabert et al[93], 1990Symptoms of anorexia followed by seizures and psychosisTemporo-basalAngioma
Nagaratnam et al[94], 1990Paranoid delusionsLeft frontal lobeVenous angioma
Ko et al[57], 1989Paranoid ideation, irritability, short-term memory difficultiesLeft parieto-occipital metastatic lesionOrigin in right kidneyNo surgical intervention due to advanced stage
Dyck[95], 1985Auditory hallucinationsSylvian fissureLipoma
Binder[96], 1983Sudden behavioral changes followed by paranoid delusions; no focal neurologic signsRight lateral ventricleMeningiomaComplete resolution of symptoms after surgical intervention
Binder[96], 1983New-onset rage attacks on background of chronic schizophreniaBilateral occipitalMeningiomaResolution of rage attacks after surgical removal
Dunn et al[97], 1983Peduncular hallucinationsMidbrain compressionCystic craniopharyngiomaPrompt resolution after drainage of cyst
Soulairac et al[98], 1979Peduncular hallucinosisRight temporalAstrocytoma
Buchanan et al[99], 1975Pressured speech, hypomania, persecutory delusionsLateral ventricleMeningioma
Blustein et al[73], 1972Thought disorder, auditory hallucinationsLeft parieto-occipitalPorencephalic cyst

Another common psychiatric presentation of brain tumors is hallucinations and psychosis. Madhusoodanan et al[4] reported that while mood symptoms are the most common, being reported in 36% of the cases, psychotic symptoms were found in 22% of patients. In these cases of psychotic symptoms, the tumors were found in cerebral cortical, pituitary, pineal and posterior locations. Among these, pituitary gland was the most common location for psychotic symptoms. However, in another study, temporal lobe tumors were closely related to psychotic manifestations[8].

Personality changes (Table 5)
Table 5 Brain tumors and personality changes[41].
Ref.Psychiatric symptomsTumor locationTumor typeRemarks
Lajara-Nanson[100], 2000Personality changes and hypersexual behaviorVentricularVentricular cystImprovement with surgery
Paul et al[101], 2000Personality changes, memory impairment, poor concentrationExtramedullary with infiltration of the cerebral duraPlasmacytoma
Fahy et al[102], 1995Frontal lobe symptoms in absence of neurological signsFrontalMeningioma
Jones[103], 1993Personality changes, aggressive behavior, and emotional labilityVentricularVentricular cystsImprovement with surgery
Fulton et al[55], 1992Personality changes, walking difficulties, incontinence, neurologic signsFrontal lobeMultiple metastasesPoor response to steroid treatment
Fulton et al[55], 1992Bizarre, disinhibited behavior, neurologic signsMultiple left orbito-frontal and right thalamusAstrocytomaPoor response to steroid treatment
Fulton et al[55], 1992Withdrawn, inappropriate behavior, neurologic signsBifrontalUnknownPoor response to steroid treatment
Lobosky[104], 1984Personality changes and emotional labilityVentricularVentricular cystsImprovement with surgery
Barbizet et al[66], 1982Rage attacks, Bulimia, uninhibited and brutal sexual behavior, periods of depression with suicide attemptsFronto-temporalAstrocytoma

Frontal lobe lesions and ventricular cysts may present with personality changes. This may include disinhibition, hypersexuality, and aggressive behaviors.

Eating disorders (Table 6)
Table 6 Brain tumors and eating disorders[41].
Ref.Psychiatric symptomsTumor locationTumor typeRemarks
Vad Winkler et al[105], 2009Eating disorderPituitary glandCraniopharyngiomaImprovement with surgery
Vad Winkler et al[105], 2009Eating disorderThird ventricleCraniopharyngiomaDeveloped pituitary deficiency after surgery
Houy et al[106], 2007Anorexia nervosaFrontal side of the right sylvian valleyCavernous hemangiomaImprovement with surgery
Lin et al[107], 2003Anorexia nervosaHypothalamic region, third ventricle, pineal region, lateral ventricle, corpus callosumUnknown
Wolańczyk et al[108], 1997Anorexia nervosa, delusions, catatoniaRight parietal lobeArachnoid cyst
Chipkevitch et al[54], 1993Atypical anorexia nervosa, depressive symptomsHypothalamusTeratoma
Berek et al[109], 1991Anorexia nervosaThird ventricleTeratoma
Trabert et al[93], 1990Symptoms of anorexia followed by seizures and psychosisTemporo-basalAngioma
Climo[110], 1982Anorexia nervosaHypothalamusCraniopharyngioma
Weller et al[111], 1982Anorexia nervosaPineal glandPinealoma
Goldney[112], 1978Anorexia nervosaHypothalamusCraniopharyngioma
Swann[113], 1977Anorexia nervosaHypothalamusPinealoma
White et al[114], 1977Anorexia nervosaHypothalamusGlioma
Heron et al[115], 1976Anorexia nervosaHypothalamusUnknown
Daly et al[116], 1973Anorexia nervosaHypothalamusEctopic pinealoma

Weight loss and decreased appetite are associated with different types of malignancies, and in patients with brain tumors it may be among the first warning signs. This may be mistaken for symptoms of anorexia nervosa, particularly in young females, and can lead to a misdiagnosis. A review by Madhusoodanan et al[4] on associations between tumor locations and psychiatric symptoms concluded that while anorexic symptoms may be a result of tumors in numerous locations in the brain, hypothalamic neoplasms most commonly present as anorexia symptoms.

Miscellaneous symptoms (Table 7)
Table 7 Brain tumors and miscellaneous symptoms[41].
Ref.Psychiatric symptomsTumor locationTumor typeRemarks
Feng et al[20], 2013Anomic aphasiaLeft temporal lobeGlioblastoma multiformeNo resolution of aphasia after surgical treatment
Hoffmann et al[117], 2012Crying, spitting, biting self and others, mutism, withdrawal, sleepiness, anergia, bipolar affective disorderPituitary glandCraniopharyngiomaNo resolution of symptoms after surgery
Wong et al[118], 2012Attacks of sensory overload and unusual familiarityLeft temporal lobeEpidermoid tumor
Rosenzweig et al[119], 2010Epilepsy, paroxysmal ictal phonemesLeft superior temporal gyrusAngiocentric glioma grade IResolution of symptoms after surgery
Tsutsumi et al[21], 2008Abnormal laughter, left-hemiparesisRight frontal lobeGlioblastoma multiformeResolution of psychiatric symptoms after surgical treatment
Sokolski et al[120], 2003Breakthrough manic symptoms with mild nausea and dizzy spells, daily derealisation episodes with olfactory aurasRight medial temporal, displacing right ventricle and right hippocampusGrade IV invasive astrocytomaImprovement of psychiatric symptoms with surgical resection
Burns et al[121], 2003New-onset pedophiliaRight orbito-frontalUnknown
Daigneault et al[122], 1999Aggression, precocious puberty and worsening seizuresHypothalamicHamartoma
Konovalov et al[123], 1998Korsakoff’s syndromeThird ventricleColloid cystComplete resolution after surgical removal
Caplan et al[124], 1992Intractable seizures followed by coprolalia, compulsive behaviors, aphasiaLeft anterior temporalGanglionomaSymptoms subsided after surgical resection
Ko et al[57], 1989Expressive aphasia, short-term memory difficulties, no focal neurologic signsMultiple metastatic left fronto-parietal lesionsOrigin in right lung
Ko et al[57], 1989Deteriorating memory and disorientation to time and place, behavioral changes, visual agnosia, aphasia, self-neglectLeft parietal extending to temporal lobe with midline shiftUnknown-surgery refused- no autopsy report given
Ribeiro et al[125], 1989Bonnet syndrome, blindnessPosterior parasagittalMeningioma
Durst et al[126], 1988KoroCorpus callosumLipoma or dermoid tumor
Binder[96], 1983Behavioral changes, confusion with neurological signs developing after 24 hLeft thalamicGlioblastoma multiforme
de Bures et al[127], 1982Aggressive behavior, cognitive impairment on background of chronic alcohol abuse and head injuriesLeft temporalAstrocytoma

There are some cases of patients with brain tumors who present with a more ambiguous psychiatric history and progression of illness. Feng et al[20] described an 86-year-old female who presented with anomic aphasia. The patient reportedly had difficulty naming familiar objects and people for month. Her neurological exam was normal and she did not have any symptoms aside from the anomic aphasia. A brain computed tomography (CT) and magnetic resonance imaging (MRI) showed a large tumor in the left temporal lobe, compressing the left lateral ventricle and causing a midline shift. She underwent surgical resection of the tumor and radiotherapy. Pathology reports showed that the tumor was a glioblastoma multiforme. In this case, surgery and radiotherapy did not result in resolution of the anomic aphasia.

Among other less common and atypical psychiatric manifestations of brain tumor is a case of pathological laughter reported by Tsutsumi et al[21]. A 60-year-old female presented with abnormal laughter and left-hemiparesis. Her laughter was induced by non-specific stimuli and lasted for a few minutes. The MRI showed a ring-enhanced lesion in the subcortical area of the right frontal lobe along with extensive perifocal brain edema. Upon total resection of the tumor, glioblastoma multiforme was diagnosed. Two weeks post-operative follow-up showed resolution of her pathological laughter and hemiparesis.

DIAGNOSIS

Brain tumors as the primary cause of psychiatric symptoms are a rare occurrence. The rarity of this condition, insidiousness of the disease process, vague symptomatology, variety of signs pointing to several causative factors all contribute to the diagnostic challenges. Diagnosis of psychiatric symptoms being secondary to brain tumors starts from having the clinical suspicion. Early diagnosis is critical with regards to further treatment and better quality of life[1].

A thorough medical history and physical examination may assist in the diagnosis. Subtle clues that could otherwise be missed include neurologic signs: apraxia, visual field deficits, and anomia. Personality changes, sleep disturbances, apathy, weight loss, anorexia, or faltering concentration may be the first presentation of the illness. Further clues that suggest the presence of brain tumors may include psychiatric symptoms that do not fall into distinct diagnostic categories or atypical symptoms, symptoms that are refractory to treatment, and recurrence of previously controlled symptoms where other contributory factors (such as non-adherence to treatment, acute stressors, or medication changes) have been ruled out[1].

Neuroimaging is the primary diagnostic modality used to visualize the presence of brain tumors. CT and MRI are used for anatomical assessments. Magnetic resonance spectroscopy is used for the relative quantification of metabolites in different brain locations. Studies of neuronal activity related to local cerebral blood flow are done by functional MRI (fMRI). Positron emission tomography and single-photon emission computed tomography provide images by use of radionuclides[22]. For the purpose of this article, we will focus on the anatomical assessments that are routinely used in clinical practice. CT remains the modality of choice for trauma and acute hemorrhage. Its other advantages include: greater availability, fewer contraindications, and less expense. MRI offers higher resolution and is useful in evaluating necrosis, hemorrhage, cysts, tumors, and white-matter changes. It is generally superior to CT in visualizing brain tumors or other soft-tissue lesions. Functional studies are mostly used in the research setting and presently do not appear to have major advantages over CT and MRI for routine clinical setting. This may change with further refinements and clinical utility[22].

Madhusoodanan et al[1] recommended that neuroimaging be considered in the following conditions: new-onset psychosis, new-onset mood/memory symptoms, occurrence of new or atypical symptoms, new-onset personality changes, and anorexia without body dysmorphic symptoms. Conditions wherein neuroimaging may or may not be required include recurrence of previously controlled psychiatric symptoms and patients that are refractory to treatment[1].

Neuropsychological testing is useful in evaluating cognitive and neuropsychological dysfunction, in documenting changes pre- and post-treatment, and in monitoring the effectiveness of rehabilitative efforts[2].

MANAGEMENT

Removal of the tumor may completely resolve the psychiatric or behavioral symptoms. Otherwise, decreasing the size of the tumor or halting its growth may also decrease these symptoms. Additionally, treating the acute mass effects such as increased intracranial pressure or hydrocephalus may improve cognitive functioning and decrease behavioral symptoms[2].

Neuropsychiatric and behavioral symptoms can persist or worsen after these interventions. Pharmacological and psychotherapeutic measures can be instituted to improve the functioning and quality of life[2].

Pharmacological management follows general therapeutic principles of tumor-free patients with similar symptoms. However, patients with brain tumors may have increased susceptibility for delirium, seizures, medication side effects, and drug-drug interactions.

Antidepressants may be beneficial in patients presenting primarily with depressive symptoms. Selective serotonin reuptake inhibitors (SSRIs) have a favorable side effect profile and less potential to cause delirium. Maprotiline and bupropion appear to have higher risk for seizures[23]. Methylphenidate has also been shown to be effective in patients with secondary depression. It was well tolerated and did not appear to have an increased risk for seizures. It was also found to be effective in patients with apathy syndrome aside from depression[24].

Mood stabilizers are useful in treating manic symptoms. Lithium may cause delirium and lower seizure threshold. Valproate, carbamazepine, oxcarbazepine, benzodiazepines, and gabapentin, having anticonvulsant properties, may be preferable alternatives[2]. A recent review explored possible neuroprotective effects of lithium in patients with brain cancer, especially when treated with radiation. Possible targets of lithium may include excitotoxicity, excessive apoptosis, reduced neurogenesis, and senescence of growth and regeneration. This effect has been shown in preliminary studies, but more research is required to confirm its benefits and clinical utility[25].

Antipsychotics may be used for treating psychotic syndromes with hallucinations, delusions, and disturbances in thought content and processes. First-generation antipsychotics were more widely used. Lower potency antipsychotics like chlorpromazine and thioridazine may be associated with increased risk for seizures and delirium. High-potency antipsychotics such as fluphenazine and haloperidol have lesser risk for seizure and delirium. First-generation antipsychotics like haloperidol and fluphenazine have a higher potential for extrapyramidal symptoms. This can be minimized by lowering the dosages or the addition of antiparkinsonian agents such as benztropine or trihexyphenidyl. However, addition of these agents also increases the risk for anticholinergic delirium. The second-generation antipsychotics may be preferred because of lower incidence of some of these side-effects. Effectiveness of these agents has been noted in some case reports[26,27]. However, clozapine and olanzapine are also associated with higher risk for seizures and delirium[28].

Other treatment modalities include electro-convulsive therapy (ECT). This may be given consideration in cases of refractory depression. Brain tumors without increased intracranial pressure (ICP) or edema can be treated safely with ECT[29-32] when appropriate precautions have been taken. Daily neurological evaluations are of paramount importance as deterioration may be subtle. High-risk patients are those with presence of large mass or multiple masses, increased intracranial pressure, edema, or mass effect. In these patients, ECT may be considered only if they are severely ill, or there is risk for harm to self or others, and other options have failed. Measures to reduce edema and the increase in ICP should be undertaken. Regardless of the risks of ECT, all patients undergoing this treatment should have ongoing consultation with the neurologist/neurosurgeon. Additionally, changes in the lesion should be taken into account during maintenance treatments, as low-risk patients may progress to high-risk[33].

Psychotherapy is also an important treatment modality. This helps to improve overall functional status, interpersonal and psychosocial stressors, and emotional and cognitive status. Anxiety and depressive symptoms are frequently present and may benefit from supportive and cognitive therapy, and psychoeducation. This is supported by a study which found that the presence of depressive symptoms was the most important predictor of quality of life among patients with brain tumors[34]. It is also important to improve coping strategies and identify maladaptive defenses that may interfere with somatic treatments[2].

DISCUSSION

Diagnosis and treatment of psychiatric symptoms of brain tumors are challenging. At initial presentation, patients may have a variety of symptoms or a clinical picture that do not fit into a diagnostic category. Symptoms may be vague, such as apathy syndrome or personality changes, or symptoms that are refractory to treatment. Psychiatric symptoms may be the only presenting symptoms of a brain tumor. These symptoms tend not to be localized to specific anatomical regions and tumors are not confined to specific subdivisions. Tumors also exert effects by pressure, edema, and diaschisis (affecting connections to distant areas of the brain). Thus, psychiatric symptoms generally have no localizing value. A possible exception as previously discussed, is hypothalamic tumors that present with anorexia without distorted body image. Neuroimaging, pituitary hormone levels, and ophthalmologic evaluation are recommended based on the symptomatology to rule out the presence of a tumor[1,4].

Various studies describe the impact of tumor location and the variety of symptoms. Dorsolateral tumors lead to difficulties with organization and planning. Orbito-frontal tumors cause disinhibition, and medial frontal tumors cause apathy and abulia. Frontal tumors may exhibit personality changes in the patient. Diencephalic and pituitary lesions lead to vegetative symptoms. More specifically, diencephalic lesions manifest hypersomnic and hyperphagic variants of depressive disorders[8-10,35,36].

A thorough history and physical examination, high degree of clinical suspicion, and neuroimaging are keys to the diagnosis. A review[37] was conducted on the clinical- and cost-effectiveness of structural imaging (by use of CT or MRI) in patients with psychosis, especially that of first-episode psychosis. It concluded that structural neuroimaging adds little clinical information not suspected on history and physical examination that would influence management. Routine neuroimaging is not recommended.

Brain tumors may be primary or secondary, and are treated accordingly either by surgery, radiation, or chemotherapy. After the treatment of the tumor, psychiatric symptoms may either resolve or persist. From our clinical experience, we advocate that the treatment of psychiatric symptoms may begin before the treatment of the brain tumor, to improve the quality of life and coping skills. The psychotropics may be tapered gradually and discontinued after the tumor treatment. If psychiatric symptoms recur, psychotropics may be reinstated.

Studies of anxiety, depression, and somatic symptoms in brain tumors are complicated because it is unclear whether they are caused by the tumor or is a psychological response to the stress secondary to the diagnosis or treatment. Compounding the clinical conundrum is the lack of large controlled studies evaluating the psychiatric symptoms of brain tumors or their treatment modalities. Due to the relative rarity of this presentation and the wide array of manifestations, information regarding treatment is mostly derived from case reports or case series. Furthermore, the descriptions of psychiatric symptoms are not uniform in the literature. All these factors contribute to the difficulties in the analysis and extrapolation of available information. Treatment options include pharmacotherapy, psychotherapy, and ECT as discussed earlier.

A review that attempted to delineate the role of antidepressants in patients with brain tumors was unable to make recommendations due to lack of appropriate studies and cautions about the assumption of efficacy in this patient population[38]. With regards to safety, a study of SSRIs in patients with glioblastoma multiforme found neither any increased toxicity nor adverse effects on survival[39]. Methylphenidate has shown some evidence of efficacy in improving cognitive function and motivation. The side effects were minimal[24]. However, a more recent prospective, placebo-controlled trial of prophylactic d-threo-methylphenidate did not show any improvement in quality of life, with the main outcome measure being improvements in fatigue[40].

Continued treatment for persistent psychiatric symptoms is also complicated by the potential for delirium and seizures, possible side effects, drug-drug interactions, and status of the tumor and its treatment. Steroids may be associated with depression and psychosis. It is important that the treatment should be based on a multi-disciplinary team approach. Clinical specialists involved in the treatment should work closely and be aware of these issues with continued treatment, rehabilitation, and quality of life.

CONCLUSION

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 presenting with new-onset psychosis or mood/memory symptoms, occurrence of new or atypical symptoms, personality changes, and anorexia without body dysmorphic symptoms. Treatment is geared towards the tumor, its complications, and the psychiatric symptoms. Management of persistent psychiatric symptoms is based on extrapolation of limited evidence, assessment of risk vs benefits, and understanding of potential complications related to the disease and concomitant therapy. Further investigation is needed to improve our understanding of the mechanisms by which tumors produce psychiatric symptoms. This may lead to improved understanding of the mechanisms of psychiatric disorders, advanced diagnostic modalities, better categorization of symptom constructs, and prospective trials for the management of the psychiatric symptoms in patients with brain tumors. With improvements in imaging techniques and diagnostic categorization of psychiatric symptoms, studies of correlation of anatomic location or neuronal functional groups and psychiatric symptoms may yield associations not previously found.

Footnotes

P- Reviewer: Lu RB S- Editor: Ji FF L- Editor: A E- Editor: Wu HL

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