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Late onset mania as an organic syndrome: A review of case reports in the literature
Journal of Affective Disorders 188 (2015) 226–231
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Late onset mania as an organic syndrome: A review of case reports in the literature Musa Sami a,b, Hina Khan c, Ramin Nilforooshan d,n a
Kent & Medway Partnership Trust, UK Institute of Psychiatry, Psychology & Neuroscience, King’s College, London, UK c East Kent University Hospitals NHS Trust, UK d Surrey & Borders NHS Partnership Trust, Brain Science Research Unit, ACU, Holloway Hill, Lyne, Chertsey Surrey KT16 0AE, UK b
art ic l e i nf o
a b s t r a c t
Article history: Received 5 May 2015 Received in revised form 7 July 2015 Accepted 12 August 2015 Available online 8 September 2015
Aims: Although First Episode Mania presenting over the age of 50 is reported in several cases, there has been little systematic compilation of these case reports. We report a review of case reports on these subjects. Methods: We undertook a literature search on MEDLINE, PsychInfo and EMBASE to identify case reports of first episode of mania or hypomania presenting over the age of 50. Results: 35 cases were identified. 29/35 (82%) had a suspected underlying organic cause. Organic causes included vascular causes, iatrogenic drug use, electrolyte imbalance, dementia and thyroid disease. Vascular risk factors were present in 17/35 cases (48%). In 10/35 (28%) of cases organic treatment contributed to successful remission of the manic episode. Limitations: As evidently not all cases have been reported the main limitation is that of publication bias for this paper. Any such hypothesis generated from studying these cases would require replication in prospective longitudinal trials of this cohort of patients. Conclusions: This review of case reports appears to add to evidence of late onset mania having an organic basis. Whether this is a separate organic syndrome remains to be established. Our provisional findings suggest that such patients should have a thorough medical and psychiatric screening in identifying an underlying cause. & 2015 Elsevier B.V. All rights reserved.
Keywords: Late-life Mania Hypomania Geriatric First-episode
1. Introduction Late onset mania is an infrequent but serious illness characterised by: (i) distinct episode of manic or hypomanic illness presenting over the age of 50 and (ii) absence of a previous history of manic episode (Dols et al., 2014; Van Gerpen et al., 1999). Late onset mania is thus not the same as manic illness in the elderly, which may have a late (age4 50) or early (oage50) onset. Late onset mania is also different from late onset bipolar illness, and does not require a depressive episode, although, evidently some patients with late onset mania will turn out to have a bipolar illness(Depp and Jeste, 2004; Vasudev and Thomas, 2010). A recent meta-analysis noted manic illness to affect 6% of psychiatric inpatients over the age of 50 (Dols et al., 2014). Around half suffer from late onset mania: with one 5-year study reporting inpatient admissions in 9 out of 284 admissions (3%), whereas another reported 25 such patients out of 744 (3%)(Benedetti et al., n
Corresponding author. Fax: þ44 1932 875128. E-mail address: [email protected] (R. Nilforooshan).
http://dx.doi.org/10.1016/j.jad.2015.08.027 0165-0327/& 2015 Elsevier B.V. All rights reserved.
2008; Ramirez-Bermudez, 2011). One study estimated a community incidence of 0.6% of a manic episode in the Canadian elderly (Préville et al., 2008), but this does not differentiate between late and early onset. One early compilation of case reports of patients with ‘secondary mania’ noted a later age of onset(Krauthammer and Klerman, 1978) and, despite only reporting on 6 patients over the age of 50, subsequently a link was made between late onset illness and secondary causes. Retrospective case-note reviews and case series suggest that vascular injury, neurological illness, iatrogenic drug use and vascular risk factors are associated with late onset presentations(Subramaniam et al., 2007; Tohen et al., 1994; Young et al., 2003). However such work to date has had limitations: several papers have defined late-onset as variously between the ages of 20–45 (Benazzi, 2000; Chu et al., 2010; Depp et al., 2004; Lehmann and Rabins, 2006; Martino et al., 2013), thus limiting genarisability to older populations. Of studies which have had an appropriate age cut-off, most have often struggled to recruit late onset participants: reporting small groups of between 6 and 20 participants in the late onset cohort (Hays et al., 1998; Montes et al., 2013; Subramaniam et al., 2007; Tohen et al., 1994; Young
Table 1 Features of Late Onset Mania Treatment Given: Age of onset
Psychosis
Postulated causative factor
Gammon (1980)
53
Wright and Sllvoe (1988) Drake et al. (1990)
73 52
Drake et al. (1990)
56
Left ventral pons infarction
Kubacki (1991) Lovestone (1991)
72 67
Antidepressant
Kellner and Neher (1991) Cooper et al. (1994)
81
Evans and Marshall (1995) Davidoff et al. (1996)
62
Habib et al. (1998) Habib et al. (1998)
73 79
Hypercalcaemia secondary to thiazide therapy
Auditory hallucinations, Paranoid delusions
Right ventral pons infarction
Family History
MMSE Neuroleptic
Y
Lithium
Alcohol misuse
Depression Late-onset Schizophrenia
Y Y Y
52
67
Psychiatric History
Learning Disability, Down's syndrome Autoimmune thrombocytopaenia Auditory hallucinations, paranoid delusions
Antidepressant medication
Depression
Y
Depression
30/30 19/30
Dementia
Y
Chlopromazine and lithium carbonate Clonazepam Lithium and carbamazepine
Y
Y
Haloperidol then thioradizine
Y
Lithium, perphenazine and clonazepam Valproic acid Lithium then valproic acid and risperidone Haloperidol, sodium valproate then lorazepam and thioridazine Valproic acid Haloperidol, thioridazine, then lorazepam, buspirone Lithium then olanzapine
Y
59
Depression
Y
Donovan and Freudenreich (2007) Appleby and Rosenberg (2007) Tor et al. (2007)
67
Critical Right Carotid Artery stenosis
Depression
76
Alzhiemers dementia
Depression
21/30
Valroproate and biperiden then clozapine and clonazepam, then lamotrogine and lithium Aripiprazole and clonazepam then lamotrogine Various mood stabilisers
72
Autoimmune hypothyroidism
Depression
29/30
Haloperidol
Lopez et al. (2009)
61
Thalamic ischaemia and Antidepressant
Depression
23/30
Murru et al. (2009)
91
Amaladoss and Le Claire (2010)
69
19/30
Risperidone, then valproate and quetiapine Valproate, quetiapine ECT, sertraline, trazadone Clozapine
Prabhakar and Balon (2010) McKnight and Hampson (2011) DeKay and Matuszak (2011) Liang and Yang (2011)
76
28/30
Risperidone
Grandiose and paranoid delusions Bizarre delusions, thought disorder, auditory hallucinations Auditory hallucinations, delusions
65 68 75
Grandiose delusions, delusions of infidelity
Pancreatic neoplasm
30/30
Lacunar infarcts in bilateral thalami (vascular dementia)
Anxiety & Psychotic Depression
White Matter Hyperintensities and Antidepressant medication Hyponatraemia
Psychotic Illness
Chemotherapy (docetaxel and cisplatin) þ steroids Cryptococcal meningitis
Y
Risperidone and sertraline Various then olanzapine Risperidone
Y
Stopped iatrogenic agent
Y Y Y Y
Thyroid correction (carbimazole)
Y Y Y Y
Carotid endarterectomy
Y Y
Thyroid correction (thyroxine)
Y Y Y Y
Stopped iatrogenic agent Electrolyte correction Stopped iatrogenic agent Treatment of
Y Y Y Y
227
Depression
Senturk et al. (2006)
Bilateral extensive white matter hyperintensities and Nortryptilene Prodromal Vascular Dementia
Auditory hallucinations, grandiose delusions
Y N
Haloperidol, maprotiline, carbemazepine Chlopromazine
61
27/30
Y
Haloperidol and lithium
Zanetti et al. (2007)
Auditory & visual hallucinations, grandiose and persecutory delusions
Electrolyte correction
Y
Stroke of left insular cortex and left basal ganglia 26/30
Remission?
Lithium and the fluphenzaine
Fenn and George 78 (1999) Schreiner et al. (2001) 81 Nath and Sagar (2001) 65
Hyperthyroid
Organic
M. Sami et al. / Journal of Affective Disorders 188 (2015) 226–231
Case
Y Y Y
Y 51
70 83 53 Achalia et al. (2014) Routh and Hill (2014) Park et al. (2014)
79
70's
Rosenzweig et al. (2011) Medjugorac and Horvat (2011) Tseng and Tzeng (2012) Antelmi et al. (2014)
62
74 Yeh and Peng (2011)
Grandiose delusions Paranoid delusions
Hyponatraemia Haemmorhagic stoke of thalamus Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
Lacunar infarcts in basal ganglia
Depression
Alzheimer's Dementia Rivastigmine
Fentanyl induced
Grandiose delusions, thought disorder
Multiple infarcts right cerebral hemisphere Depression and Sertraline withdrawel Chemotherapy - carbotaxel
Y
29/30
Valproic acid, quetiapine and venlafaxine Sodium valproate and olanzapine Electrolyte correction Haloperidol then olanzapine Quetiapine and benzodiazepines 28/30
17/30
29/30
28/30
Y Haloperidol and diazepam
Y
Y Quetiapine and valproate
Stopped iatrogenic agent
Y infection 28/30
Organic MMSE Neuroleptic Age of onset Case
Table 1 (continued )
Psychosis
Postulated causative factor
Psychiatric History
Family History
Treatment Given:
Valproic acid and quetiapine
M. Sami et al. / Journal of Affective Disorders 188 (2015) 226–231
Remission?
228
et al., 2003), and furthermore not all such studies have differentiated between late onset mania with late onset bipolar. One large prospective study has been undertaken with late onset age defined 450, with an adequately sized group (n ¼143) but does not specifically look at the organicity of the condition and looked at bipolar disorder onset rather than late onset mania (Oostervink et al., 2009). A further retrospective review, with 30 late onset patients in an inpatient group did consider vascular risk factors, but again focussed on bipolar disorder rather than mania (Wylie et al., 1999). There thus exists limited direct evidence for the organic or non-organic nature of late onset manic illness. Research on the area has been described as ‘sparse’ and ‘understudied’ (Azorin et al., 2012; Dols et al., 2014). Although a single case report is of limited generalisability, a review of case reports may help provide leads for further research. We thus aimed to compile published case reports to review evidence for the organic nature of manic illness in the elderly.
2. Methods We undertook a literature search on MEDLINE, PsychInfo and EMBASE comprising the following terms: (bipolar OR mani* OR hypomani*) AND (old OR elderly OR “old age” OR geria*) AND (“first episode” OR “first-episode” OR “lateonset” OR “late onset”) Studies were limited to the English language and human studies without date restriction. Databases were searched through to the 2nd week of August 2014. The Inclusion Criteria identified were: (1) published case reports (2) of patients with a manic or hypomanic episode presenting over the age of 50 (3) without previous history of manic episode. Exclusion criteria were: (1) cases where the onset of mania or hypomania was unclear and (2) cases were the age of first episode was not specified. Data were extracted from cases regarding age of onset of manic episode, symptomatology, past psychiatric, medical, medication and family history. If the mania was thought to be secondary the causative factors were also noted. Data on the treatment strategy (whether organic or psychiatric), neuroleptic medication used, imaging results and success of treatment were also extracted. The salient presenting features of each case report were extracted and reviewed by authors to determine they fulfilled criteria for the manic episode. We also extracted whether an operationalized definition from the International Classification of Diseases (ICD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM) was noted in the case report. We further noted whether delirium had been excluded in each case.
3. Results Out of 644 papers identified, 44 identified case reports. 33 papers fit the inclusion criteria detailing information on 35 cases (Achalia et al., 2014; Amaladoss and Le Claire, 2010; Antelmi et al., 2013; Appleby and Rosenberg, 2007; Cooper et al., 1994; Davidoff et al., 1996; DeKay and Matuszak, 2011; Donovan and Freudenreich, 2007; Drake et al., 1990; Evans and Marshall, 1995; Fenn and George, 1999; Gammon and Docherty, 1980; Habib et al., 1998; Kellner and Neher, 1991; Kubacki, 1991; Liang and Yang, 2011; López et al., 2009; Lovestone, 1991; McKnight and Hampson, 2011; Medjugorac and Horvat, 2011; Murru et al., 2009; Nath and Sagar, 2001; Park et al., 2014; Prabhakar and Balon, 2010; Rosenzweig et al., 2011; Routh and Hill, 2014; Schreiner et al., 2001; Senturk et al., 2006; Tor et al., 2007; Tseng and Tzeng, 2012; Wright and SIlvoe, 1988; Yeh and Peng, 2011; Zanetti et al., 2007). Reasons for
M. Sami et al. / Journal of Affective Disorders 188 (2015) 226–231
exclusions of cases were: insufficient detail (n ¼7), diagnosis of fronto-temporal dementia (n ¼2), previous manic episode before age of 50 (n ¼1) and paper not in english (n ¼1) Results can be seen in Table 1. Of the 35 cases described, the age of onset ranged from 51 to 91 with a mean 68.5 years. Most cases appeared to cluster between the ages of 60 and 79 (24/35 cases (69%)). Psychotic features were described in 11/35 cases (31%) of cases. All cases of psychosis involved either paranoid or grandiose delusions. Auditory hallucinations were a feature of 6/35 (17%) of cases whereas visual hallucinations featured in one case. 29 out of 35 cases had a postulated organic cause described in the case report (82%). In 13 cases this was vascular (37%); in 11 cases were described as drug-induced (31%), including antidepressants in 5 cases (14%). In 3 cases an electrolyte imbalance was implicated (9%), whereas dementia was implicated in 3 cases (9%). In 17/35 cases (49%) a previous psychiatric history other than mania or hypomania was reported. In 12 cases (34%) the patients had a history of depression, which was itself mostly later onset: having come on after the age of 40 in 9/12 (75%) of cases and after the age of 50 in 7/12 (58%). Other preceding psychiatric morbidity reported included: learning disability (one case), Alzheimer’s disease (one case), alcohol excess (one case), and late onset psychosis (two cases). In 9/35 cases (25%) a family history of psychiatric disorder was present, including any reported Axis I disorder in both first and second degree relatives. In only 3 cases (9%) was a family history reported of first degree relatives with bipolar or psychotic illness. There was a high burden of chronic physical disease reported.18 patients out of 35 (51%) had established risk factors for vascular disease (hypertension: 12 cases (34%); cardiovascular disease 5 cases (14%); diabetes mellitus 6 cases (17%); hyperlipidaemia 3 cases (9%); obesity 1 case (3%); or previous stroke 3 cases (9%)). Four cases had a history of malignancy (11%). Imaging results were undertaken in 30 cases through a variety of imaging techniques including CT, MRI and FDG-PET. Focal lesions were reported in 17/30 cases. In 6/30 cases basal ganglia involvement was reported (20%), and in the same number (6/30 (20%)) there was frontal lobe involvement. 5/30 cases reported imaging abnormalities in the thalamus (17%). Most cases had a favourable outcome. 34 out of 35 cases reported improvement in symptomatology with treatment (97%). Most reported successful psychopharmacological treatment using conventional mood stabiliser and/or antipsychotic medication. In a smaller number of cases treatment success was attributed to organic causes (stopping of causative medication, correction of electrolyte imbalance, treatment of thyroid problem and revascularisation).
4. Discussion Although several different types of bipolar affective disorder have been described; late onset mania is not clearly a separate category. To date the six types formally described have been: Type I: typical intermittent manic and depressive episodes; Type II: cyclothymia with hypomania; Type III: depression with drug induced hypomania; Type IV: a late onset depression superimposed on a hyperthymic temperament; Type V: repeated episodes of depression on a family history of depression; and Type VI: late onset mood episodes manifesting as cognitive impairment and dementia(Akiskal and Pinto, 1999; Azorin et al., 2012; Ng et al., 2008). Several of our cases could be classified according to this – with 34% of cases having had a prior depressive episode. However, it is worthwhile to see if late onset manic episodes have
229
Table 2 Proposed Work-up for presentations of Late-Onset Mania. Indication 1. History: Full Personal Psychiatric History Family History Medical & Physical Health History Current and Past Medications 2. Examinations: Mental State Examination Cognitive Examination (MMSE) Physical and Neurology Examination 3. Baseline ECG 4. Urine Dip 5. Blood tests: Full Blood Count Urea & Electrolytes and Calcium Thyroid Liver Function CRP 6. Screening of vascular risk factors Weight/BMI Smoking history Consider cholesterol and diabetes screening 6. Neuroimaging: MRI (preferred) / CT
Bipolar Disorder/Mood/Thought Disorder
Vascular Risk factors Antidepressant/Opiates/Steroids/Chemotherapy
Dementia (Alzheimer’s, Vascular, Mixed, Frontotemporal), Delirium Baseline QTc, Atrial Fibrillation (vascular risk) Urinary Tract Infection Baseline, Infection, thrombocytopaenia Electrolyte imbalance Hyper/hypo-thyroidism Baseline, marker of alcohol misuse Infection Vascular Burden
Frontotemporal and other dementia, Infarct, Haemmorhage, Tumour, Infection, Generalised/ Focal Atrophy 7. Other tests (only if indicated) Physician/Neurologist Consultation Autoantibodies Auto-antibody Encephalitis Lumbar Puncture Meningitis Further imaging as advised
distinguishing features, relating to a possible organic nature. Of particular interest is the high degree of physical co-morbidity and vascular injury. This is supported by several aspects of the cases reported: comorbidities such as stroke leading to manic episode; shared risk factors with vascular disorders such as hyperlipidaemia and diabetes. Based on the varied causative syndromes of cases reported, we propose a basic investigative physical work-up in patients presenting with late onset mania (see Table 2). This must not neglect the essential aspect of thorough history taking to identify potential causative factors. In addition to screening for various causes identified in the case reports, we also add a baseline electrocardiogram, in case of prescription for psychotropic medications, and screening for delirium using CRP and urine dip. Given the high degree of cases identified with silent or lacunar infarcts, imaging is a necessity in these patients. We report on focal imaging lesions in 17 out of 35 reported cases (49%). However, the true proportion may be higher: at least 17/30 (57%), since imaging was not undertaken in 5 cases. Furthermore of the 13 cases identified without abnormality, 12 were CT scans. It is likely that had MRI been undertaken in these cases, other focal abnormalities would have been identified, since MRI is more sensitive in detecting White Matter Hyperintensites particularly in the deep subcortical structures (McDonald et al., 1991). Previous imaging studies have demonstrated increased White Matter Hyperintensities particularly in frontal and basal ganglia areas, similar to our findings (Besga et al., 2011; Tamashiro et al., 2008). Given our findings, we further propose thalamic infarcts a region of further study as thalamic lesions were a feature of five
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M. Sami et al. / Journal of Affective Disorders 188 (2015) 226–231
cases (14%). Notably we report a favourable 98% partial to full remission rate of the manic episode. Although we must accept a degree of selection bias, this appears to compare favourably with reported recovery rates of 58–84% after first manic episode at 6 months in traditional bipolar populations (McMurrich et al., 2012). In our case review treatment of the underlying organic cause is thought to be a factor in improvement in upto 28% of cases. Whether late onset mania is an organic disorder with a distinct course from functional illness remains open to debate. This study does demonstrate some evidence for an organic nature: there is a high prevalence of vascular and physical comorbidity and imaging abnormalities. This paper also demonstrates that treatment of the organic cause (e.g. cessation of iatrogenic medication, correction of electrolyte or metabolic abnormality, treatment of infection and in one case revascularisation) can contribute to successful management of manic episode. However, there are also indications that late onset mania may be part of the bipolar spectrum – 34% of cases had a history of prior depression and thus would fulfil the criteria for bipolar disorder. Clinical features also seem to be similar to those previously reported in bipolar mania – our review reports 31% of cases with psychotic features, in keeping with rates previously described (18–65%) (Dunayevich and Keck, 2000). Furthermore we report a high remission rate with conventional psychotropic medications. Further work in prospective cohort studies, looking at a range of demographic, clinical, imaging characteristics and treatment outcomes is required to more definitively delineate the issues in the organic versus functional debate. 4.1. Limitations By compiling and reviewing case reports we are able to obtain a large amount of information relating to aetiological, prognostic and imaging results. However, as evidently not all cases have been reported we must accept the possibility of publication bias as a limitation in this paper. Any such hypothesis generated from studying these cases would require replication in prospective longitudinal trials of this cohort of patients. A further limitation is that of collection of cases only published in the English language. Nonetheless, by collating a variety of postulated organic causes in late onset mania, this paper provides preliminary evidence of the organic origins of the condition with 29/35 cases (82%) have a reported direct organic cause.
5. Conclusion Our review of published case reports appears to add to evidence of late onset mania having an organic basis. Whether this is a distinct syndrome requires further study. We propose that such patients have a thorough psychiatric and medical screen in looking to determine an underlying cause. More follow-up prospective studies on patients presenting with late onset mania are needed to look at long-term outcome and determine optimum management.
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Late onset mania as an organic syndrome: A review of case reports in the literature Musa Sami a,b, Hina Khan c, Ramin Nilforooshan d,n a
Kent & Medway Partnership Trust, UK Institute of Psychiatry, Psychology & Neuroscience, King’s College, London, UK c East Kent University Hospitals NHS Trust, UK d Surrey & Borders NHS Partnership Trust, Brain Science Research Unit, ACU, Holloway Hill, Lyne, Chertsey Surrey KT16 0AE, UK b
art ic l e i nf o
a b s t r a c t
Article history: Received 5 May 2015 Received in revised form 7 July 2015 Accepted 12 August 2015 Available online 8 September 2015
Aims: Although First Episode Mania presenting over the age of 50 is reported in several cases, there has been little systematic compilation of these case reports. We report a review of case reports on these subjects. Methods: We undertook a literature search on MEDLINE, PsychInfo and EMBASE to identify case reports of first episode of mania or hypomania presenting over the age of 50. Results: 35 cases were identified. 29/35 (82%) had a suspected underlying organic cause. Organic causes included vascular causes, iatrogenic drug use, electrolyte imbalance, dementia and thyroid disease. Vascular risk factors were present in 17/35 cases (48%). In 10/35 (28%) of cases organic treatment contributed to successful remission of the manic episode. Limitations: As evidently not all cases have been reported the main limitation is that of publication bias for this paper. Any such hypothesis generated from studying these cases would require replication in prospective longitudinal trials of this cohort of patients. Conclusions: This review of case reports appears to add to evidence of late onset mania having an organic basis. Whether this is a separate organic syndrome remains to be established. Our provisional findings suggest that such patients should have a thorough medical and psychiatric screening in identifying an underlying cause. & 2015 Elsevier B.V. All rights reserved.
Keywords: Late-life Mania Hypomania Geriatric First-episode
1. Introduction Late onset mania is an infrequent but serious illness characterised by: (i) distinct episode of manic or hypomanic illness presenting over the age of 50 and (ii) absence of a previous history of manic episode (Dols et al., 2014; Van Gerpen et al., 1999). Late onset mania is thus not the same as manic illness in the elderly, which may have a late (age4 50) or early (oage50) onset. Late onset mania is also different from late onset bipolar illness, and does not require a depressive episode, although, evidently some patients with late onset mania will turn out to have a bipolar illness(Depp and Jeste, 2004; Vasudev and Thomas, 2010). A recent meta-analysis noted manic illness to affect 6% of psychiatric inpatients over the age of 50 (Dols et al., 2014). Around half suffer from late onset mania: with one 5-year study reporting inpatient admissions in 9 out of 284 admissions (3%), whereas another reported 25 such patients out of 744 (3%)(Benedetti et al., n
Corresponding author. Fax: þ44 1932 875128. E-mail address: [email protected] (R. Nilforooshan).
http://dx.doi.org/10.1016/j.jad.2015.08.027 0165-0327/& 2015 Elsevier B.V. All rights reserved.
2008; Ramirez-Bermudez, 2011). One study estimated a community incidence of 0.6% of a manic episode in the Canadian elderly (Préville et al., 2008), but this does not differentiate between late and early onset. One early compilation of case reports of patients with ‘secondary mania’ noted a later age of onset(Krauthammer and Klerman, 1978) and, despite only reporting on 6 patients over the age of 50, subsequently a link was made between late onset illness and secondary causes. Retrospective case-note reviews and case series suggest that vascular injury, neurological illness, iatrogenic drug use and vascular risk factors are associated with late onset presentations(Subramaniam et al., 2007; Tohen et al., 1994; Young et al., 2003). However such work to date has had limitations: several papers have defined late-onset as variously between the ages of 20–45 (Benazzi, 2000; Chu et al., 2010; Depp et al., 2004; Lehmann and Rabins, 2006; Martino et al., 2013), thus limiting genarisability to older populations. Of studies which have had an appropriate age cut-off, most have often struggled to recruit late onset participants: reporting small groups of between 6 and 20 participants in the late onset cohort (Hays et al., 1998; Montes et al., 2013; Subramaniam et al., 2007; Tohen et al., 1994; Young
Table 1 Features of Late Onset Mania Treatment Given: Age of onset
Psychosis
Postulated causative factor
Gammon (1980)
53
Wright and Sllvoe (1988) Drake et al. (1990)
73 52
Drake et al. (1990)
56
Left ventral pons infarction
Kubacki (1991) Lovestone (1991)
72 67
Antidepressant
Kellner and Neher (1991) Cooper et al. (1994)
81
Evans and Marshall (1995) Davidoff et al. (1996)
62
Habib et al. (1998) Habib et al. (1998)
73 79
Hypercalcaemia secondary to thiazide therapy
Auditory hallucinations, Paranoid delusions
Right ventral pons infarction
Family History
MMSE Neuroleptic
Y
Lithium
Alcohol misuse
Depression Late-onset Schizophrenia
Y Y Y
52
67
Psychiatric History
Learning Disability, Down's syndrome Autoimmune thrombocytopaenia Auditory hallucinations, paranoid delusions
Antidepressant medication
Depression
Y
Depression
30/30 19/30
Dementia
Y
Chlopromazine and lithium carbonate Clonazepam Lithium and carbamazepine
Y
Y
Haloperidol then thioradizine
Y
Lithium, perphenazine and clonazepam Valproic acid Lithium then valproic acid and risperidone Haloperidol, sodium valproate then lorazepam and thioridazine Valproic acid Haloperidol, thioridazine, then lorazepam, buspirone Lithium then olanzapine
Y
59
Depression
Y
Donovan and Freudenreich (2007) Appleby and Rosenberg (2007) Tor et al. (2007)
67
Critical Right Carotid Artery stenosis
Depression
76
Alzhiemers dementia
Depression
21/30
Valroproate and biperiden then clozapine and clonazepam, then lamotrogine and lithium Aripiprazole and clonazepam then lamotrogine Various mood stabilisers
72
Autoimmune hypothyroidism
Depression
29/30
Haloperidol
Lopez et al. (2009)
61
Thalamic ischaemia and Antidepressant
Depression
23/30
Murru et al. (2009)
91
Amaladoss and Le Claire (2010)
69
19/30
Risperidone, then valproate and quetiapine Valproate, quetiapine ECT, sertraline, trazadone Clozapine
Prabhakar and Balon (2010) McKnight and Hampson (2011) DeKay and Matuszak (2011) Liang and Yang (2011)
76
28/30
Risperidone
Grandiose and paranoid delusions Bizarre delusions, thought disorder, auditory hallucinations Auditory hallucinations, delusions
65 68 75
Grandiose delusions, delusions of infidelity
Pancreatic neoplasm
30/30
Lacunar infarcts in bilateral thalami (vascular dementia)
Anxiety & Psychotic Depression
White Matter Hyperintensities and Antidepressant medication Hyponatraemia
Psychotic Illness
Chemotherapy (docetaxel and cisplatin) þ steroids Cryptococcal meningitis
Y
Risperidone and sertraline Various then olanzapine Risperidone
Y
Stopped iatrogenic agent
Y Y Y Y
Thyroid correction (carbimazole)
Y Y Y Y
Carotid endarterectomy
Y Y
Thyroid correction (thyroxine)
Y Y Y Y
Stopped iatrogenic agent Electrolyte correction Stopped iatrogenic agent Treatment of
Y Y Y Y
227
Depression
Senturk et al. (2006)
Bilateral extensive white matter hyperintensities and Nortryptilene Prodromal Vascular Dementia
Auditory hallucinations, grandiose delusions
Y N
Haloperidol, maprotiline, carbemazepine Chlopromazine
61
27/30
Y
Haloperidol and lithium
Zanetti et al. (2007)
Auditory & visual hallucinations, grandiose and persecutory delusions
Electrolyte correction
Y
Stroke of left insular cortex and left basal ganglia 26/30
Remission?
Lithium and the fluphenzaine
Fenn and George 78 (1999) Schreiner et al. (2001) 81 Nath and Sagar (2001) 65
Hyperthyroid
Organic
M. Sami et al. / Journal of Affective Disorders 188 (2015) 226–231
Case
Y Y Y
Y 51
70 83 53 Achalia et al. (2014) Routh and Hill (2014) Park et al. (2014)
79
70's
Rosenzweig et al. (2011) Medjugorac and Horvat (2011) Tseng and Tzeng (2012) Antelmi et al. (2014)
62
74 Yeh and Peng (2011)
Grandiose delusions Paranoid delusions
Hyponatraemia Haemmorhagic stoke of thalamus Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
Lacunar infarcts in basal ganglia
Depression
Alzheimer's Dementia Rivastigmine
Fentanyl induced
Grandiose delusions, thought disorder
Multiple infarcts right cerebral hemisphere Depression and Sertraline withdrawel Chemotherapy - carbotaxel
Y
29/30
Valproic acid, quetiapine and venlafaxine Sodium valproate and olanzapine Electrolyte correction Haloperidol then olanzapine Quetiapine and benzodiazepines 28/30
17/30
29/30
28/30
Y Haloperidol and diazepam
Y
Y Quetiapine and valproate
Stopped iatrogenic agent
Y infection 28/30
Organic MMSE Neuroleptic Age of onset Case
Table 1 (continued )
Psychosis
Postulated causative factor
Psychiatric History
Family History
Treatment Given:
Valproic acid and quetiapine
M. Sami et al. / Journal of Affective Disorders 188 (2015) 226–231
Remission?
228
et al., 2003), and furthermore not all such studies have differentiated between late onset mania with late onset bipolar. One large prospective study has been undertaken with late onset age defined 450, with an adequately sized group (n ¼143) but does not specifically look at the organicity of the condition and looked at bipolar disorder onset rather than late onset mania (Oostervink et al., 2009). A further retrospective review, with 30 late onset patients in an inpatient group did consider vascular risk factors, but again focussed on bipolar disorder rather than mania (Wylie et al., 1999). There thus exists limited direct evidence for the organic or non-organic nature of late onset manic illness. Research on the area has been described as ‘sparse’ and ‘understudied’ (Azorin et al., 2012; Dols et al., 2014). Although a single case report is of limited generalisability, a review of case reports may help provide leads for further research. We thus aimed to compile published case reports to review evidence for the organic nature of manic illness in the elderly.
2. Methods We undertook a literature search on MEDLINE, PsychInfo and EMBASE comprising the following terms: (bipolar OR mani* OR hypomani*) AND (old OR elderly OR “old age” OR geria*) AND (“first episode” OR “first-episode” OR “lateonset” OR “late onset”) Studies were limited to the English language and human studies without date restriction. Databases were searched through to the 2nd week of August 2014. The Inclusion Criteria identified were: (1) published case reports (2) of patients with a manic or hypomanic episode presenting over the age of 50 (3) without previous history of manic episode. Exclusion criteria were: (1) cases where the onset of mania or hypomania was unclear and (2) cases were the age of first episode was not specified. Data were extracted from cases regarding age of onset of manic episode, symptomatology, past psychiatric, medical, medication and family history. If the mania was thought to be secondary the causative factors were also noted. Data on the treatment strategy (whether organic or psychiatric), neuroleptic medication used, imaging results and success of treatment were also extracted. The salient presenting features of each case report were extracted and reviewed by authors to determine they fulfilled criteria for the manic episode. We also extracted whether an operationalized definition from the International Classification of Diseases (ICD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM) was noted in the case report. We further noted whether delirium had been excluded in each case.
3. Results Out of 644 papers identified, 44 identified case reports. 33 papers fit the inclusion criteria detailing information on 35 cases (Achalia et al., 2014; Amaladoss and Le Claire, 2010; Antelmi et al., 2013; Appleby and Rosenberg, 2007; Cooper et al., 1994; Davidoff et al., 1996; DeKay and Matuszak, 2011; Donovan and Freudenreich, 2007; Drake et al., 1990; Evans and Marshall, 1995; Fenn and George, 1999; Gammon and Docherty, 1980; Habib et al., 1998; Kellner and Neher, 1991; Kubacki, 1991; Liang and Yang, 2011; López et al., 2009; Lovestone, 1991; McKnight and Hampson, 2011; Medjugorac and Horvat, 2011; Murru et al., 2009; Nath and Sagar, 2001; Park et al., 2014; Prabhakar and Balon, 2010; Rosenzweig et al., 2011; Routh and Hill, 2014; Schreiner et al., 2001; Senturk et al., 2006; Tor et al., 2007; Tseng and Tzeng, 2012; Wright and SIlvoe, 1988; Yeh and Peng, 2011; Zanetti et al., 2007). Reasons for
M. Sami et al. / Journal of Affective Disorders 188 (2015) 226–231
exclusions of cases were: insufficient detail (n ¼7), diagnosis of fronto-temporal dementia (n ¼2), previous manic episode before age of 50 (n ¼1) and paper not in english (n ¼1) Results can be seen in Table 1. Of the 35 cases described, the age of onset ranged from 51 to 91 with a mean 68.5 years. Most cases appeared to cluster between the ages of 60 and 79 (24/35 cases (69%)). Psychotic features were described in 11/35 cases (31%) of cases. All cases of psychosis involved either paranoid or grandiose delusions. Auditory hallucinations were a feature of 6/35 (17%) of cases whereas visual hallucinations featured in one case. 29 out of 35 cases had a postulated organic cause described in the case report (82%). In 13 cases this was vascular (37%); in 11 cases were described as drug-induced (31%), including antidepressants in 5 cases (14%). In 3 cases an electrolyte imbalance was implicated (9%), whereas dementia was implicated in 3 cases (9%). In 17/35 cases (49%) a previous psychiatric history other than mania or hypomania was reported. In 12 cases (34%) the patients had a history of depression, which was itself mostly later onset: having come on after the age of 40 in 9/12 (75%) of cases and after the age of 50 in 7/12 (58%). Other preceding psychiatric morbidity reported included: learning disability (one case), Alzheimer’s disease (one case), alcohol excess (one case), and late onset psychosis (two cases). In 9/35 cases (25%) a family history of psychiatric disorder was present, including any reported Axis I disorder in both first and second degree relatives. In only 3 cases (9%) was a family history reported of first degree relatives with bipolar or psychotic illness. There was a high burden of chronic physical disease reported.18 patients out of 35 (51%) had established risk factors for vascular disease (hypertension: 12 cases (34%); cardiovascular disease 5 cases (14%); diabetes mellitus 6 cases (17%); hyperlipidaemia 3 cases (9%); obesity 1 case (3%); or previous stroke 3 cases (9%)). Four cases had a history of malignancy (11%). Imaging results were undertaken in 30 cases through a variety of imaging techniques including CT, MRI and FDG-PET. Focal lesions were reported in 17/30 cases. In 6/30 cases basal ganglia involvement was reported (20%), and in the same number (6/30 (20%)) there was frontal lobe involvement. 5/30 cases reported imaging abnormalities in the thalamus (17%). Most cases had a favourable outcome. 34 out of 35 cases reported improvement in symptomatology with treatment (97%). Most reported successful psychopharmacological treatment using conventional mood stabiliser and/or antipsychotic medication. In a smaller number of cases treatment success was attributed to organic causes (stopping of causative medication, correction of electrolyte imbalance, treatment of thyroid problem and revascularisation).
4. Discussion Although several different types of bipolar affective disorder have been described; late onset mania is not clearly a separate category. To date the six types formally described have been: Type I: typical intermittent manic and depressive episodes; Type II: cyclothymia with hypomania; Type III: depression with drug induced hypomania; Type IV: a late onset depression superimposed on a hyperthymic temperament; Type V: repeated episodes of depression on a family history of depression; and Type VI: late onset mood episodes manifesting as cognitive impairment and dementia(Akiskal and Pinto, 1999; Azorin et al., 2012; Ng et al., 2008). Several of our cases could be classified according to this – with 34% of cases having had a prior depressive episode. However, it is worthwhile to see if late onset manic episodes have
229
Table 2 Proposed Work-up for presentations of Late-Onset Mania. Indication 1. History: Full Personal Psychiatric History Family History Medical & Physical Health History Current and Past Medications 2. Examinations: Mental State Examination Cognitive Examination (MMSE) Physical and Neurology Examination 3. Baseline ECG 4. Urine Dip 5. Blood tests: Full Blood Count Urea & Electrolytes and Calcium Thyroid Liver Function CRP 6. Screening of vascular risk factors Weight/BMI Smoking history Consider cholesterol and diabetes screening 6. Neuroimaging: MRI (preferred) / CT
Bipolar Disorder/Mood/Thought Disorder
Vascular Risk factors Antidepressant/Opiates/Steroids/Chemotherapy
Dementia (Alzheimer’s, Vascular, Mixed, Frontotemporal), Delirium Baseline QTc, Atrial Fibrillation (vascular risk) Urinary Tract Infection Baseline, Infection, thrombocytopaenia Electrolyte imbalance Hyper/hypo-thyroidism Baseline, marker of alcohol misuse Infection Vascular Burden
Frontotemporal and other dementia, Infarct, Haemmorhage, Tumour, Infection, Generalised/ Focal Atrophy 7. Other tests (only if indicated) Physician/Neurologist Consultation Autoantibodies Auto-antibody Encephalitis Lumbar Puncture Meningitis Further imaging as advised
distinguishing features, relating to a possible organic nature. Of particular interest is the high degree of physical co-morbidity and vascular injury. This is supported by several aspects of the cases reported: comorbidities such as stroke leading to manic episode; shared risk factors with vascular disorders such as hyperlipidaemia and diabetes. Based on the varied causative syndromes of cases reported, we propose a basic investigative physical work-up in patients presenting with late onset mania (see Table 2). This must not neglect the essential aspect of thorough history taking to identify potential causative factors. In addition to screening for various causes identified in the case reports, we also add a baseline electrocardiogram, in case of prescription for psychotropic medications, and screening for delirium using CRP and urine dip. Given the high degree of cases identified with silent or lacunar infarcts, imaging is a necessity in these patients. We report on focal imaging lesions in 17 out of 35 reported cases (49%). However, the true proportion may be higher: at least 17/30 (57%), since imaging was not undertaken in 5 cases. Furthermore of the 13 cases identified without abnormality, 12 were CT scans. It is likely that had MRI been undertaken in these cases, other focal abnormalities would have been identified, since MRI is more sensitive in detecting White Matter Hyperintensites particularly in the deep subcortical structures (McDonald et al., 1991). Previous imaging studies have demonstrated increased White Matter Hyperintensities particularly in frontal and basal ganglia areas, similar to our findings (Besga et al., 2011; Tamashiro et al., 2008). Given our findings, we further propose thalamic infarcts a region of further study as thalamic lesions were a feature of five
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cases (14%). Notably we report a favourable 98% partial to full remission rate of the manic episode. Although we must accept a degree of selection bias, this appears to compare favourably with reported recovery rates of 58–84% after first manic episode at 6 months in traditional bipolar populations (McMurrich et al., 2012). In our case review treatment of the underlying organic cause is thought to be a factor in improvement in upto 28% of cases. Whether late onset mania is an organic disorder with a distinct course from functional illness remains open to debate. This study does demonstrate some evidence for an organic nature: there is a high prevalence of vascular and physical comorbidity and imaging abnormalities. This paper also demonstrates that treatment of the organic cause (e.g. cessation of iatrogenic medication, correction of electrolyte or metabolic abnormality, treatment of infection and in one case revascularisation) can contribute to successful management of manic episode. However, there are also indications that late onset mania may be part of the bipolar spectrum – 34% of cases had a history of prior depression and thus would fulfil the criteria for bipolar disorder. Clinical features also seem to be similar to those previously reported in bipolar mania – our review reports 31% of cases with psychotic features, in keeping with rates previously described (18–65%) (Dunayevich and Keck, 2000). Furthermore we report a high remission rate with conventional psychotropic medications. Further work in prospective cohort studies, looking at a range of demographic, clinical, imaging characteristics and treatment outcomes is required to more definitively delineate the issues in the organic versus functional debate. 4.1. Limitations By compiling and reviewing case reports we are able to obtain a large amount of information relating to aetiological, prognostic and imaging results. However, as evidently not all cases have been reported we must accept the possibility of publication bias as a limitation in this paper. Any such hypothesis generated from studying these cases would require replication in prospective longitudinal trials of this cohort of patients. A further limitation is that of collection of cases only published in the English language. Nonetheless, by collating a variety of postulated organic causes in late onset mania, this paper provides preliminary evidence of the organic origins of the condition with 29/35 cases (82%) have a reported direct organic cause.
5. Conclusion Our review of published case reports appears to add to evidence of late onset mania having an organic basis. Whether this is a distinct syndrome requires further study. We propose that such patients have a thorough psychiatric and medical screen in looking to determine an underlying cause. More follow-up prospective studies on patients presenting with late onset mania are needed to look at long-term outcome and determine optimum management.
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