Volume 3, 2018, 18-24

REVIEW ARTICLE

Psychiatric aspects of tumours of the

Nuno Madeira* Pedro Oliveira Psychiatry Department, Centro Hospitalar e Universitário de Coimbra; Faculty of Medicine, University of Coimbra

Tiago Santos Department of Psychiatry and Mental Health, Baixo Vouga Hospital Centre

Emília Albuquerque Psychiatry Unit, Francisco Gentil Portuguese Institute of Oncology, Coimbra

Abstract: The incidence of tumours has increased in recent years. They represent the second most common cause of death attributable to neurological conditions. Although expansive brain lesions often lead to observation by or Neurosurgery, it is not uncommon for psychiatric symptoms to be the reason for initial contact with medical care. Brain tumours may present as symptomatology similar to the so-called primary, or functional, psychiatric disorders. However, in contrast to psychiatric disease in other types of cancer, where adjustment disorders predominate, organic are the most frequent diagnosis in patients with CNS tumours. Anatomic location represents one of several factors that contribute to the nature and severity of psychiatric conditions. Tumours of the are more frequently associated with changes in executive function, amotivational and personality changes. Temporal tumours can trigger psychotic symptoms such as hallucinations and delusions. The treatment of the symptomatology will essentially involve removal of the lesion whenever possible. Nevertheless, symptomatic treatment of psychiatric manifestations should always take place. Psychopharmacology, psychotherapy and psychoeducation of caregivers are the best modes of treatment.

Keywords: Central Nervous System ; Psycho-oncology; Psychiatric Symptoms

Introduction rior fossa, the most common supratentorial lesions being Psycho-oncology spans the two principal psychiatric and those of the frontal (22%) and temporal lobes (22%); 12% psychological dimensions of cancer: on the one hand, the are located in the parietal lobes, 10% in the sella turcica, experiences of patients and their family members over the and 4% in the occipital cortex 2 . course of the disease, and also the stress felt by care-giv- Cerebral metastases generally manifest as hemiparesis ing professionals; on the other, the psychological, behav- and cognitive dysfunction; unilateral hypoesthesia, atax- ioural and social factors that influence risk, detection and ia and are less common symptoms 3 . The usual survival of oncological disease 1 . symptomatology of primary brain tumours – solid tu- The incidence of brain tumours has increased in recent years. mours or lymphomas – is cognitive dysfunction, head- They represent the second most common cause of death at- aches, vomiting, seizures and focal deficits 4 . Disease tributable to neurological causes, the first being 2 . progression and the toxic effects of treatment (e.g. radio- Brain tumours can be classified according to their nature therapy) tend to cause cognitive deterioration to worsen (primary or metastatic), histology or location. Gliomas and, at advanced stages, demential syndromes or changes (40-55%) and meningiomas (10-20%) represent the ma- in consciousness. jority of expansive intracerebral lesions. Metastatic le- While expansive brain lesions often lead to observation by sions (15-25%) originate most commonly from lung and Neurology or Neurosurgery, it is not uncommon for initial breast tumours. 30% of tumours are located in the poste- contact with medical care to be prompted by psychiatric symptoms. A study of 530 patients with brain tumours re- * Correspondence to: [email protected] ported that in 18% of cases clinical presentation was psy- Psychiatric aspects of tumours of the central nervous system 19 chiatric 5 . A recent analysis of patients with meningiomas medial syndrome, which manifests above all as , indicated that 21% of the study sample had initially pre- is usually related to tumour lesions of midline structures sented with psychiatric symptoms in the absence of neu- (, third ventricle, hypothalamus and pituitary), rological signs 6 . and also occurs following bilateral occlusion of the ante- rior cerebral arteries and bilateral thalamic infarcts. Lastly, Clinical Aspects orbitofrontal syndrome, in which changes in behaviour Brain tumours may present in the form of symptoms and pragmatics are to the fore, is associated with tumours similar to primary, or functional, psychiatric disorders. (e.g. inferior frontal meningiomas), as well as post-trau- However, in contrast with what happens with regard to matic lesions, vascular lesions of the anterior cerebral ar- psychiatric illness in other types of cancer, where ad- tery, multiple sclerosis and fronto-temporal dementia 8 . justment disorders predominate, organic syndromes are the most common diagnosis in patients with tumours of Table 1. Frontal syndromes the CNS. DORSOLATERAL syndrome Although some symptoms or syndromes may be associ- Predominant involvement of . ated with dysfunction of certain parts of the brain (e.g. Poor planning depression and personality changes in frontal tumours and Reduced mental flexibility psychosis in temporal lesions), anatomic location repre- Abstraction deficit sents one of several factors that contribute to the nature Persistence and severity of the psychiatric picture. Fast-growing tu- Apathy Distractibility mours are more frequently associated with agitation and Personal neglect psychosis, and more obvious cognitive dysfunction. Less Behaviours directed at stimuli aggressive lesions are associated with apathy, depression and incomplete personality changes. Multiple tumour sites VENTROMEDIAL syndrome tend to cause more significant behavioural changes. In- Deficit of initiative and motivation. creased intracranial pressure, a non-specific consequence Apathy of tumours of the CNS, is associated with apathy, depres- Incontinence sion, irritability, agitation and changes of consciousness. Gait changes Silent onset and few symptoms are a feature of the evo- lution of tumours of certain regions of the brain; lesions ORBITOFRONTAL syndrome of the anterior part of the frontal lobes, the corpus callo- Predominance of personality changes. sum, the non-dominant parietal and temporal cortex and Deterioration of social pragmatics the posterior fossa are examples of this 2 . Disinhibition Impulsiveness Moria (foolish euphoria) Frontal Lesions Emotional lability The frontal lobe constitutes the most recently evolved re- Distractibility gion of the brain in phylogenetic terms and the largest in Olfactory changes the central nervous system, representing 1/3 of its total volume. From the anatomo-functional point of view, the This anatomo-functional division is rarely clear in clin- frontal lobe is divided into at least five specialised regions: ical practice: pure presentations of these syndromes are (1) motor cortex, (2) pre-motor cortex, (3) frontal opercu- uncommon. In addition, personality changes, particular- lum, (4) para-olfactory or subcallosal zone and (5) pre- ly associated with frontal lesions (more than 70% of cas- frontal cortex. The pre-frontal cortex is the region of the es), may occur in disorders of diencephalic and temporal frontal lobe most commonly related to metacognitive abil- structures. ities, executive functions and social behaviour in general. Psychotic symptoms may be present in 10% of frontal tu- It can be divided into three distinct zones, which corre- mours. Delusions are usually fragmented and hallucina- spond to the dorsolateral, orbitofrontal and frontomedial tions are rarely auditory and complex, in contrast to what cortex. In general terms, we can organise the nature of the is most characteristic of schizophrenic psychosis 2 . deficits resulting from lesions in accordance with the pro- posed division of the pre-frontal cortex by establishing the Temporal lesions existence of three syndromes – see Table 1. 7 In addition to frequent symptoms of the ictal sphere, tu- Dorsolateral, or disorganised, syndrome, characterised mours of the temporal region have in the past been associ- by impairment of executive functions, is due in the major- ated with psychotic symptoms of a schizophreniform type. ity of cases to tumour lesions, ischaemic lesions, trauma However, more recent reports have described atypical or neurodegenerative disease of the frontal lobe 8 . Ventro- symptoms, not always associated with : vis- 20 Nuno Madeira | Pedro Oliveira | Tiago Santos | Emília Albuquerque ual, olfactory or tactile hallucinations, and mood swings Onset of symptoms is acute or subacute, and the latter are with suicidal behaviours, with conserved affect and social transient and reversible. These chronological characteris- interaction. tics help differentiate it from demential syndrome. In their Behavioural symptoms are common in temporal lesions: early stages, cases of hypoactive may be inter- personality changes have been described in more than preted as depression. In rare situations, delirium may be the 50% of patients. As described in lesions of the frontal initial manifestation of neoplastic lesions in the CNS 15 . lobe, psychiatric symptoms like apathy, irritability and The approach to delirium includes from the start identify- emotional lability occur. Anxiety is also present in more ing and correcting, wherever possible, underlying causes than 30% of cases 2 . (see Table 2).

Parietal and occipital lesions Table 2. Causes of delirium in the oncological patient Lesions of the parietal or occipital cortex have been as- Direct brain Primary brain tumour, cerebral sociated with psychiatric symptoms to a lesser degree. metastasis Parietal lesions are usually associated with perceptual and Metabolic encephalopa- Liver, kidney, lung, thyroid, motor impairments, such as and agraphes- thy due to organ failure adrenal 9 thesia, , anosognosia, acalculia and dysgraphia . Electrolyte Sodium, potassium, calcium, 25% of patients with occipital tumours present visual disturbances glucose hallucinations – generally simple, e.g. luminous flashes. Toxic effects of Narcotic analgesics, Other symptoms that have been reported – agitation, irri- treatment anticholinergics, antihistamines, tability, drowsiness – probably reflect non-specific man- corticosteroids, phenothiazines, ifestations of intracranial hypertension. In addition to chemotherapy agents, radiotherapy typical findings like homonymous hemianopia, visual ag- Infection Septicaemia 2 nosia and are also common . Haematological Anaemia (microcytic, macrocytic), disturbances coagulopathy Lesions of other structures Nutrition Malnutrition, ↓thiamine, ↓folic Diencephalic tumours often compromise structures con- acid or ↓vitamin B12 tiguous with the limbic system; it is also common for Other , constipation, paraneoplastic cortico-subcortical circuits to be affected, with subse- syndromes 10 quent psychiatric manifestations. Schizophreniform , (Adapted from Breitbart and Cohen, 1998) affective 11 and obsessive-compulsive type symptoms 12 13 and personality changes have been reported. Behav- Support measures may be sufficient, in particular environ- ioural changes are usual in lesions of the corpus callo- mental optimisation: quiet rooms with soft lighting, with sum (especially genu and splenium), with an estimated personal objects and chronological references (clock, cal- prevalence of 90%. Affective symptoms predominate; endar). The presence of family members may prove par- personality changes and psychotic symptoms are also ticularly calming. In the case of prior sensory dysfunction 2 common . Tumour lesions of the hypothalamus have requiring visual or auditory prostheses, especially in the been associated with changes of eating behaviour, in elderly, these should be available at all times. Physical particular hyperphagia; clinical observations compatible restraint, for the patient’s protection, may be used judi- with a diagnosis of anorexia nervosa have also been re- ciously. 14 ported in the literature . Subcortical tumours may pre- Support measures often prove insufficient, rendering sent with a predominance of deficits, possibly pharmacological intervention necessary. Neuroleptics, as within the framework of a subcortical-type demential dopaminergic antagonists, are the drugs of choice in symp- 2 syndrome . tomatic control of delirium (see Table 3).

Delirium Table 3. Pharmacotherapy of delirium in oncology The clinical appearance of delirium includes: prodromal Routes of Posology manifestations (restlessness, anxiety, insomnia and irri- administration tability); fluctuating evolution; distractibility; changes in state of wakefulness; disruption of sleep-wake rhythm; Haloperidol 1-5 mg, every 2-12h PO, IM, IV affective symptoms (emotional lability, sadness, distress, Chlorpromazine 25-100 mg, every 4-12h PO, IM, IV euphoria); sensoriperceptual changes (, visual and Risperidone 1-3 mg, every 12h PO, Orodisp. auditory hallucinations); paranoid delusions; disorganised Olanzapine 2.5-10 mg every 12h Orodisp. speech; temporo-spatial and autopsychic disorientation; memory impairments (especially of short-term memory). Quetiapine 25-100 mg, every 8h PO Psychiatric aspects of tumours of the central nervous system 21

Parenteral doses are approximately twice as potent as oral mer are associated with direct injury – tumoural or by ra- doses and have more rapid onset of action. Pharmacologi- diation – to specific regions, global deficits are generally cal intervention should be particularly scrupulous in ter- the consequence of diffuse effects (intracranial hyperten- minal patients, and reserved for situations of psychomotor sion and oedema), attributable to the tumour or to treat- agitation, hallucinations and paranoid delusions. ments in progress, particularly radiotherapy (Table 4). In addition to acute (e.g. oedema) and semi-acute reac- Dementia and cognitive deficit tions (e.g. demyelination), radiotherapy of brain tissue In dementia the emergence of the picture is insidious or may give rise to late reactions of the encephalopathic subacute, in contrast to delirium, from which it is further type, which occur in approximately 28% of patients 16 and differentiated by the absence of changes of consciousness are potentially fatal or irreversible. Demential syndromes and by lesser disruption of sleep-wake rhythm. that arise after radiotherapy are of the subcortical type and Neurological and cognitive deficits attributable to tumour ataxia and urinary incontinence are common; the estimat- lesions of the CNS may be focal or global. While the for- ed frequency is 3% 17 .

Table 4. Post-radiotherapy organic mental syndromes Onset Symptoms Cause Evolution Acute Immediate Lethargy, headache, fever, nausea/vomiting ↑ Intracranial pressure Early 6 to 16 weeks Lethargy, headache, fever, nausea/vomiting, Cerebral oedema? Spontaneous focal neurological ss. (local RT) Demyelination? improvement Late > 6 months Focal neurological ss., headache, Encephalopathy? Severe and permanent personality changes, seizures

The impact of chemotherapy in cognitive terms, possibly causes of anxiety and depression in oncological patients underestimated if compared with the profusion of research are set out below, in Tables 5 and 6 respectively. into the effects of radiotherapy, has been highlighted re- cently. The review of neurotoxic effects of chemother- Table 5. Causes of Anxiety in the oncological patient apy agents has described a variety of syndromes, such SITUATIONAL – Communication of diagnosis, as central and peripheral neuropathies, encephalopathy, discussion of prognosis leukoencephalopathy, ototoxicity and cerebellar symp- – Crisis related to disease or treatment toms 9 . Even so, available information on the cognitive – Conflict with family member or effects of chemotherapy is limited. professional Neuropsychological studies in patients with tumours of – Anticipation of a frightening procedure the CNS have shown more pronounced deficits in pa- – Waiting for results of supplementary tients with fast-growing lesions, namely glioblastoma examinations multiforme and grade III or IV astrocytomas 18 . The later- – Fear of recurrence ality of lesions has also been shown to have a functional DISEASE- – Uncontrolled pain impact, lesions on the left being associated predomi- related – Metabolic disturbances nantly with worse results in verbal tests, while lesions – Functional endocrine tumours of the right hemisphere are more damaging in tests – Paraneoplastic syndromes of performance. TREATMENT- – Frightening (e.g. MRI) or painful related procedures Mood disorders and anxiety – Anxiogenic drugs (bronchodilators, Depressive and anxiety syndromes are common in this antiemetics) population. By comparison with so-called ‘function- – Withdrawal states (opioids, benzodiazepines, alcohol) al’ forms, patients with tumours of the CNS also show – Nausea and vomiting attributable to cognitive deficits that are sometimes subtle, and psycho- chemotherapy therapeutic interventions are more difficult. In pharma- cological terms, some specificities must also be noted; Exacerbation of – Phobia (blood, needles, PRE-EXISTING claustrophobia) benzodiazepines can have paradoxical effects in these pa- ANXIETY – Panic disorder or generalised tients: low-dose antipsychotics are a viable alternative. anxiety disorder Corticotherapy, often administered at high doses, repre- – Post traumatic stress disorder sents a frequent cause of affective symptoms, and psy- – Obsessive-compulsive disorder chotic conditions are also described 4 . Other common (Adapted from Holland & Stiles, 2009) 22 Nuno Madeira | Pedro Oliveira | Tiago Santos | Emília Albuquerque

Table 6. Risk factors for depression Antipsychotics are particularly useful in situations of de- in the oncological patient lirium, and in organic syndromes with behavioural chang- – Uncontrolled pain es. The detrimental effect on the seizure threshold should be taken into consideration, especially in the class of the – Drugs phenothiazines (levomepromazine, chlorpromazine). Ex- • Corticosteroids • IFN and IL-2 trapyramidal symptoms, in particular akathisia, may oc- • Chemotherapy agents (vincristine, vinblastine, cur, especially in patients also medicated with antiemetics procarbazine, L-asparaginase) like metoclopramide. • Others: propanolol, tamoxifen, phenobarbital As regards the prescription of antidepressants (Table 7), – Metabolic disturbances selective serotonin reuptake inhibitors (SSRIs) represent • Anaemia, hypercalcaemia, ↓vit. B12, ↓folic acid a safe and well tolerated class of drugs. Their potential – Endocrine disturbances for pharmacokinetic interaction with other drugs must • Hypothyroidism (++), hyperthyroidism (-) be acknowledged, the safest of them being escitalopram, • Adrenal insufficiency citalopram and sertraline. Venlafaxine also represents a – Paraneoplastic syndrome beneficial option in these situations. The anticholinergic (Adapted from Holland & Stiles, 2009) effects of tricyclic antidepressants make them less appeal- ing in neuro-oncological patients, although their sedative Psychopharmacology and antinociceptive potential can prove useful in some The available information on the use of psychopharmaceu- situations. Thanks to its dopaminergic-modulating action, ticals in oncological patients comes above all from the clini- bupropione can be helpful against symptoms of anergia cal experience of liaison psychiatry teams, in the form of and anhedonia; at high doses (>300mg) it tends to lower isolated reports or small series, and not controlled trials. the seizure threshold, a particularly harmful effect in this The usual approach is use of small doses ab initio, with population. Trazodone, at low doses – 50 to 100 mg – that a preference for drugs that have a short half-life and no are subtherapeutic in antidepressant terms, is beneficial in metabolites. controlling insomnia.

Table 7. Antidepressants most widely used in oncology Name Starting dose (mg) Therapeutic dose (mg) Selective serotonin Citalopram 10-20 20-60 reuptake inhibitors Escitalopram 5-10 10-20 (SSRIs) Fluoxetine 20 20-40 Sertraline 25-50 50-150 Tricyclics Amitriptyline 25-50 50-150 Other Bupropione 150 150-300 Mirtazapine 15 15-45 Trazodone 50-10 150-300 Venlafaxine 37.5-75 75-225

Use of psychostimulants has been described as symp- ported. Drugs with a short half-life that do not under- tomatic treatment of and asthenia. Methylphe- go oxidative metabolism (e.g. lorazepam) should be nidate, at low doses (5 to 10 mg/day, as 2 split doses), preferred. can improve levels of attention and concentration, en- ergy and cognitive function, and the effect is particularly Psychotherapeutic Interventions rapid if compared with the more delayed effect of anti- Psychotherapy in neuro-oncological patients tends to be depressants. Insomnia, paranoid symptoms and halluci- supportive, drawing on crisis intervention and psychoe- nations can occur, generally when these drugs are used ducational techniques 4 . Crisis intervention seeks to de- at high doses. Use of psychostimulants in patients medi- velop coping in the context of specific, soluble problems; cated with procarbazine is contraindicated. its goal is a possible return to previous psychological Benzodiazepines should be used with caution in this functioning, emphasising the importance of symptomatic population, in situations of circumstantial anxiety or control as an aid to adjustment. Often, the simple expres- as coadjuvant therapy with antipsychotics when urgent sion of interest on the part of the therapist can signifi- sedation is required. Paradoxical effects have been re- cantly reduce distress in these patients. Psychiatric aspects of tumours of the central nervous system 23

Relaxation training and interventions of a cognitive-be- Provision of medical and nursing care to neuro-oncologi- havioural nature can be used where there is no significant cal patients is complex, demanding and potentially prob- cognitive compromise; they are potentially useful in con- lematic too. Healthcare professionals often have to deal trolling common symptoms that have an impact on quality with the death of their patients, and pathological reactions of life, such as headaches 4 . In patients with limitations in of loss are not uncommon 20 . Management of terminal terms of concentration and memory, a therapeutic diary care can be disturbing, and particularly therapeutic deci- can be used. Sessions tend to be brief, so as not to tire the sions in patients who are confused or whose awareness is patient, and a diary provides a means of writing down the compromised. key ideas addressed so that they can be revisited later. Some practices have been presented as beneficial in mini- Rehabilitation techniques have been developed to mitigate mising the psychosocial impact on professionals. Exam- cognitive decline. In another dimension of intervention, ples are the practice of frequent rotations, particularly of non-verbal techniques, like music and other forms of artis- nursing staff, and the existence of multidisciplinary sup- tic expression, can enable patients to express themselves port groups for professionals 21 . during phases of language compromise. The bleak prognosis often inherent makes it relevant to Conclusion tackle questions related to death and preparation for death. Psychiatric symptoms may be the only manifestation of Expressing fears and desires frequently gives the patient brain tumours. Because of the high degree of non-speci- relief from feelings of impotence and eases the inevitable ficity of the symptomatology caused, such tumours may burden of family members. be confused at an early stage with so-called functional psychiatric disorders. Thus a careful clinical assessment Psychosocial Impact on carers associated with the presence of atypical characteristics Family members of patients with tumours of the CNS at the time of presentation of symptomatology should adverse situations related to . Behavioural prompt additional investigation, with recourse in partic- changes can give rise to conflicts and counter-reactions ular to imaging examinations. Treatment of psychiatric with carers. The frequent loss of autonomy in such pa- symptoms is based on recourse to psychopharmaceuti- tients, who need care and supervision, tends to be exhaust- cals, with antipsychotics at the top of the list, psychother- ing for carers, most commonly spouses and other direct apy and psychoeducation for carers. family members. Communication can be compromised, Studying the symptomatology caused by tumours of the making the most basic interaction frustrating for patient CNS may lead to a better understanding of the physio- and family members alike. pathology of psychiatric disorders, categorisation of di- Taking these specificities into account, psychoeducation agnoses and development of new and better forms of programmes have been developed for carers of patients treatment. with tumours of the CNS 19 .

Conflicts of interest: The authors have no conflicts of interest to declare.

Sources of funding: The authors had no sources of funding to produce this paper.

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