Bipolar Disorders 2016: 18: 205–220 © 2016 John Wiley & Sons A/S

Published by John Wiley & Sons Ltd.

BIPOLAR DISORDERS

Review Article

Mania secondary to focal brain lesions:

implications for understanding the
functional neuroanatomy of bipolar
disorder
Satzer D, Bond DJ. Mania secondary to focal brain lesions: implications David Satzera and David J Bondb
for understanding the functional neuroanatomy of bipolar disorder. a
Medical School, University of Minnesota,
Bipolar Disord 2016: 18: 205–220. © 2016 John Wiley & Sons A/S. b
Department of Psychiatry, University of
Published by John Wiley & Sons Ltd. Minnesota, Minneapolis, MN, USA

Objectives: Approximately 3.5 million Americans will experience a

manic episode during their lifetimes. The most common causes are
psychiatric illnesses such as bipolar I disorder and schizoaffective
disorder, but mania can also occur secondary to neurological illnesses,
brain injury, or neurosurgical procedures.

Methods: For this narrative review, we searched Medline for articles on

the association of mania with stroke, brain tumors, traumatic brain
injury, multiple sclerosis, neurodegenerative disorders, epilepsy, and
neurosurgical interventions. We discuss the epidemiology, features, and doi: 10.1111/bdi.12387
treatment of these cases. We also review the anatomy of the lesions, in
light of what is known about the neurobiology of bipolar disorder. Key words: bipolar I disorder – brain tumor –
epilepsy – multiple sclerosis –
Results: The prevalence of mania in patients with brain lesions varies neurodegenerative disorders – neurosurgery –
widely by condition, from <2% in stroke to 31% in basal ganglia secondary mania – stroke – traumatic brain
calcification. Mania occurs most commonly with lesions affecting injury
frontal, temporal, and subcortical limbic brain areas. Right-sided lesions
causing hypo-functionality or disconnection (e.g., stroke; neoplasms) Received 3 November 2015, revised 22
and left-sided excitatory lesions (e.g., epileptogenic foci) are frequently February 2016, revised and accepted for
observed. publication 18 March 2016

Conclusions: Secondary mania should be suspected in patients with Corresponding author:

neurological deficits, histories atypical for classic bipolar disorder, and David J. Bond, M.D., Ph.D.
first manic episodes after the age of 40 years. Treatment with antimanic Laboratory for Neuropsychiatric Imaging
medications, along with specific treatment for the underlying neurologic Department of Psychiatry
condition, is typically required. Typical lesion locations fit with current University of Minnesota
models of bipolar disorder, which implicate hyperactivity of left- Room 516B
hemisphere reward-processing brain areas and hypoactivity of bilateral 717 Delaware Street, SE
prefrontal emotion-modulating regions. Lesion studies complement Minneapolis, MN 55414
these models by suggesting that right-hemisphere limbic-brain USA
hypoactivity, or a left/right imbalance, may be relevant to the Fax: +1 612-273-9779
pathophysiology of mania. E-mail: djbond@umn.edu

Mania is a ‘distinct period of abnormally and per-
sistently elevated, expansive, or irritable mood and
abnormally and persistently increased goal-
directed activity or energy’ (1). Changes in cogni-
tion (e.g., racing thoughts, impaired judgment, and
grandiosity) and appetitive behaviors (e.g., spend-
ing, sexual activity, and drug use) are also
prominent. Mania is a psychiatric emergency that
profoundly impairs functioning and can have dev-
astating financial, interpersonal, medical, and legal
consequences (2). Rapid, accurate diagnosis and
immediate implementation of effective treatment
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Satzer and Bond

are critical to resolve symptoms and minimize and (vii) neurosurgical interventions. We will
disability. examine the relative frequency of each of these
The lifetime prevalence of mania in the USA is conditions as causes of mania, and whether any
1.1% (2), meaning that 3.5 million Americans will symptom patterns distinguish them from primary
experience manic episodes. The most common mania. We will outline the challenges inherent in
causes are psychiatric illnesses such as bipolar dis- distinguishing primary and secondary manic
order (BD) type I (BD-I) and schizoaffective disor- episodes, and suggest an approach for assessing,
der, bipolar type (1). However, clinicians must be investigating, diagnosing, and treating secondary
aware that mania can also occur as a result of mania. Finally, we will review how neuroanatomi-
ingesting or withdrawing from psychoactive sub- cal lesions associated with manic syndromes relate
stances, or secondary to a number of medical con- to, and enhance our understanding of, the func-
ditions (Table 1) (3). Central nervous system tional neuroanatomy of BD-I.
lesions resulting from neurological illnesses, brain
injury, or neurosurgical procedures are among the
Methods
most common causes of secondary mania. This
paper summarizes the literature on manic episodes We constructed a narrative review based on three
occurring in the context of (i) stroke, (ii) traumatic sources of evidence for mania secondary to brain
brain injury, (iii) brain tumors, (iv) multiple sclero- lesions: (i) prevalence studies, (ii) relevant large
sis, (v) neurodegenerative disorders, (vi) epilepsy, (≥10 patients) studies examining etiology-specific
clinical and anatomic features, and (iii) a represen-
Table 1. Causes of secondary mania tative sample of the case reports describing mania
secondary to brain lesions. To access this literature,
Category Subcategory Examples we conducted a Medline search for the period 1946
Non-neurologic Endocrine Cushing syndrome
to October 2015 to locate published reports on the
(166) association between mania and the seven neurolog-
Hyperthyroidism ical conditions of interest. Search terms included
(167) secondary mania; mania and stroke; mania and
Metabolic B12 deficiency tumor; mania and traumatic brain injury; mania
(168)
Hemodialysis
and multiple sclerosis; mania and (Huntington’s
(169) disease or frontotemporal dementia or basal gan-
Medications Antidepressants glia calcification or Fahr* disease); mania and (epi-
(170) lepsy or seizure or lobectomy); and mania and
Levodopa (171) (neurosurg* or ablation or deep brain stimulation).
Corticosteroids (172)
Sympathomimetics
We scanned the bibliographies of selected papers
(173) and relevant review articles to locate other reports,
Illicit drugs Phencyclidine (PCP) including those published before 1946.
(174)
Neurologic Neoplasm Frontal lobe meningioma
(63)
Temporal lobe glioma
Results
(57) Stroke
Trauma Traumatic brain injury
(34) Epidemiology. Psychiatric syndromes are common
Vascular Ischemic stroke (9) after stroke. Foremost among these are depression
Intracerebral
hemorrhage (12)
and anxiety, which respectively affect 29–33% (4, 5)
Infection AIDS (175) and 24% (6) of patients one year or more following
Prion disease (176) stroke. Less common psychiatric sequelae include
Viral encephalitis (177) emotional lability, personality disorders, psychosis,
Neurodegenerative Frontotemporal and mania (7). Post-stroke mania is relatively rare,
dementia (78)
Huntington’s disease
with an estimated prevalence of less than 2% (8).
(84) Features. The features of post-stroke mania were
Other Epilepsy (97)
Multiple sclerosis
characterized by Santos and colleagues in a review
(67) of 74 published cases (9). Most patients were male
Neurosurgery (99) and had suffered right-sided strokes (77% right,
17% left, and 6% bilateral) (9), in keeping with pre-
The table is adapted from multiple sources (3, 178, 179); see vious reports suggesting that infarction involving
these reviews for further references.

206

right corticolimbic pathways was a risk factor for
mania (10–13). Interestingly, they found that other
putative risk factors for post-stroke mania, includ-
ing subcortical atrophy and a family history of men-
tal illness, were in fact rarely observed. All classical
features of mania were well represented, with the
core manic symptom of mood elevation being the
initial presenting symptom in 92% of patients. The
median duration of manic symptoms was 8 weeks
(range: 4–52 weeks). Among follow-up reports,
30% of patients experienced recurrent mania, and
an additional 15% had subsequent hypomanic
symptoms (9).
Lesions of the right frontal lobe and basal ganglia
are common among patients with post-stroke
mania. The most frequent cortical regions affected
are the right ventral prefrontal cortex (PFC) (14,
15) and right medial frontal lobe (13, 16). Right-
sided basal ganglia infarcts, particularly in the
caudate (14, 15) and thalamus (15, 17–19), are com-
monly associated with mania as well. Pontine
strokes have been reported in a small number of
cases (20, 21). There also exist reports of mania in
patients with left-sided lesions only (22, 23). Some
cases involve large, multifocal, or bilateral infarcts,
making it difficult to attribute manic symptoms to a
single affected structure or pathway (21, 22, 24–26).
Treatment. The available data suggest that mood-
stabilizing medications should be selected with cau-
tion in this population. Lithium has been found to
improve recovery from stroke (27, 28), while antipsy-
chotics, particularly haloperidol, may impede recov-
ery (29–31), and benzodiazepines may have mixed
effects (30–33). In practice, treatments for post-stroke
mania included mood stabilizers in 62% of patients,
typical antipsychotics in 32%, atypical antipsychotics
in 19%, and benzodiazepines in 13%
Traumatic brain injury
Epidemiology. Mania affects approximately 9% of
patients with traumatic brain injury (TBI) (34).
Furthermore, patients with newly diagnosed BD-I
are 1.5 times more likely to have suffered a head
injury within the past 5 years than the general pop-
ulation (35). Seizures and prolonged posttraumatic
amnesia have been reported to be risk factors for
mania after closed head trauma (36).
Features. The pathophysiology of mania sec-
ondary to TBI is incompletely understood, mainly
due to the heterogeneous pathology (e.g., cerebral
contusion, hemorrhage, and diffuse axonal injury)
seen in TBI. Additional proposed mechanisms
include glutamate excitotoxicity, decreased cholin-
Mania secondary to brain lesions
ergic and dopaminergic activity, and increased
serotoninergic activity (37).
Closed head injury frequently involves trauma to
the frontal and temporal poles, and lesions of the
ventral PFC and temporal cortex have frequently
been described in patients with posttraumatic mania
(11, 12, 15, 34, 38). In a longitudinal study of 66 vic-
tims of closed head trauma, Jorge et al. (34) found
that lesions of the basal temporal pole were highly
associated with mania. Interestingly, they did not
find an association between frontal lobe lesions and
mania, nor did they find a difference between left-
and right-sided lesions. Lim (39) identified three cases
of mania associated with left-hemispheric lesions in
right-handed individuals, challenging the popular
theory that secondary mania may result from dam-
age to the nondominant hemisphere. However, no
published studies report the overall proportion of
dominant-hemispheric lesions in lesion-associated
secondary mania.
Treatment. Valproate has been reported to be
effective for mania in TBI (40) and may be consid-
ered a first-line therapy (41). Lithium can impair
cognitive function and decrease the seizure thresh-
old, and is not recommended as an initial treat-
ment of mania in TBI (37). Treatment with
carbamazepine has met with mixed success (42,
43). A case report suggested that clonidine may
also reverse manic symptoms in TBI (42).
Brain tumors
Epidemiology. Over 50% of people with brain
tumors experience psychiatric symptoms (44), but
insidious tumors with psychiatric symptoms as the
presenting complaint are rare. In a case series of
323 consecutive psychiatric patients referred for
neuroimaging, only one brain tumor was identified
(45). Moreover, although a large population-based
study reported a 19-fold increased incidence of
brain tumors in people with first psychiatric presen-
tations, the low base rate of brain tumors (1/10,000
adults) meant that this still represented a very small
number of psychiatric patients (46). Brain tumors
presenting with mania are rarer still; one study
found that only 15% of brain tumor patients with
psychiatric presentations exhibited mania (47).
Features. We identified 16 case reports on mania
in people with brain tumors (48–55). Multiple
tumor types were implicated, roughly paralleling
their prevalence in the general population, suggest-
ing that tumor histology does not play a role in
mania. A large majority of the tumors (81%) were
207
Satzer and Bond
located in (or produced mass effect on) the frontal
lobe, temporal lobe, or subcortical limbic struc-
tures. An additional 13% involved the pons, which
contains serotonergic and noradrenergic cell bod-
ies. There was a strong preponderance of right-
hemisphere involvement: 75% of tumors were
right-sided, 6% were bilateral, 13% affected mid-
line structures, and only 6% were confined to the
left hemisphere.
All patients had typical manic or mixed symp-
toms. However, half were experiencing their first
mania at age 40 years or later, well outside the
usual age range in BD-I (typically 15–30 years of
age). Two patients had chronic mania (lasting 2–
8 years), which is rare in people with BD-I. Neuro-
logical signs or symptoms were present in less than
50% of the patients.
Some of the patients had experienced premorbid
mood symptoms, underscoring the challenges
inherent in diagnosing secondary mania. The fre-
quency of pre-existing depression (19%) was simi-
lar to that in the general population, but the rate of
pre-existing submanic bipolar spectrum illness [BD
type II (BD-II)], or cyclothymia; 19%, three of 16)
was substantially higher than the population rate
of 1 4%. There are two competing interpretations
of this finding: (i) a submanic bipolar diathesis
increases the risk of frank mania in people with
brain tumors, or (ii) these patients experienced
manic episodes due to progression of their bipolar
illnesses, not as a result of brain tumor. Finally,
two of the patients had a documented history of
BD-I. One decreased her dose of mood-stabilizing
medication before her index mania, raising the like-
lihood that her mania was unrelated to her brain
tumor. The second experienced a marked increase
in the frequency of mood episodes prior to being
diagnosed with an acoustic neuroma, suggesting
that brain tumors can worsen the course of BD-I.
Treatment. Seven of 11 patients for whom treat-
ment information was provided responded to
mood stabilizers and/or antipsychotics. One addi-
tional patient responded to electroconvulsive ther-
apy (ECT). Mortality was high despite surgical
resection, with four patients dying within 4 years
of the index mania. Four of six patients for whom
longer term psychiatric outcomes were reported
remained euthymic without medications for peri-
ods of 10 months to 4 years, while two improved
but did remit.
Multiple sclerosis (MS)
Epidemiology. Prevalence estimates for bipolar
syndromes in MS vary widely (64); a recent
208
Canadian population study found bipolar spec-
trum disorders in 4.7% of patients with MS,
compared to 2.3% in the general population (65).
Carta et al. (66) reported odds ratios of 44.4 and
7.4 for bipolar spectrum disorders and major
depressive disorder, respectively, indicating a par-
ticular predisposition to mania and hypomania in
MS patients. A recent large Swedish population
study found no clear temporal association
between MS and BD, despite reaffirming a strong
association between the two diagnoses. The
authors suggested that the absence of a definitive
chronological relationship suggests that occult
inflammatory processes—rather than medication,
psychological trauma, or other factors—may be
responsible for the symptoms of BD in this popu-
lation (67). It is important to note that corticos-
teroids and other medications have been
implicated in some cases (64), particularly when
mania arises immediately following the initiation
of steroid treatment (68).
Features. The high frequency of secondary mania
in MS is in keeping with the abundant data regard-
ing white matter changes in BD-I. However, no
studies have systematically examined the relation-
ship between plaque location and the presence of
manic symptoms (69), perhaps due to the inconsis-
tent relationship between plaque location and neu-
rological deficits in MS. New lesions are not
necessarily identified in patients with MS and first-
time mania, even in the absence of other clear
causes of secondary mania (e.g., recent medication
changes) (70). However, Sidhom et al. (68)
reported that one patient with MS who experi-
enced an acute manic episode had a new, active
lesion in the right orbitofrontal white matter.
Treatment. Despite the high prevalence of sec-
ondary mania/hypomania in MS, there are no pub-
lished trials of mood stabilizers or antipsychotics
in this population (64). Similar to mania in pri-
mary BD-I, mania in patients with MS is generally
treated with lithium or anticonvulsant medica-
tions. However, lithium may be poorly tolerated in
some patients due to diuresis (particularly in the
setting of neurogenic bladder) and sedation
(especially in patients prone to falls) (71). In the
case of medication-induced mania, cessation or
dosage reduction is recommended whenever
possible.
Neurodegenerative disorders
Certain degenerative disorders of the frontal lobe,
temporal lobe, and basal ganglia are strongly asso-

ciated with mania. These include frontotemporal
dementia (FTD), Huntington’s disease (HD), and
basal ganglia calcification (BGC). Compared to
the more focal lesions discussed above, these con-
ditions yield less clear information about the anat-
omy and etiology of manic symptoms, owing to
the multisystem involvement seen in neurodegener-
ative disorders.
Mania in FTD: epidemiology and features. FTD
involves pathology of the frontal and temporal
lobes, and is thus predictably associated with sec-
ondary mania. Many reports describe an initial
‘misdiagnosis’ of BD, followed by diagnosis of
FTD via neuropsychological tests and neuroimag-
ing (72–75). Compared to patients with other
types of dementia, patients with FTD are twice as
likely to be diagnosed with BD (76) and exhibit
greater elation and disinhibition in neuropsychi-
atric testing (77). Liu et al. (78) found that these
symptoms were associated with frontal and tem-
poral variants of FTD. They did not observe
specific anatomic correlates of elation, but disinhi-
bition was associated with lower right-sided vol-
umes in the ventromedial PFC, anterior temporal
cortex, and amygdala (78). A conflicting study
reported that increased positive emotional reactiv-
ity was associated with decreased left-sided ventro-
lateral PFC, ventromedial PFC, anterior insula,
and striatum volumes (79). Case reports have
linked acquired extraversion and other manic
behaviors with bilateral temporal lobe degenera-
tion and relative sparing of the frontal lobes (80).
Woolley and colleagues contend that behavioral-
variant FTD can be distinguished from primary
mania by the progressive, unremitting manic
symptoms rather than the discrete manic episodes
typical of BD-I (76).
Mania in HD: epidemiology and features. HD most
prominently involves atrophy of the caudate
nucleus, also a common location for mania-asso-
ciated infarcts. Mood disorders are a well-recog-
nized comorbidity of HD and often precede chorea
and other motor features (81). A meta-analysis by
Mendez (82) reported a 4.8% prevalence of mania
in HD. Even in HD patients without frank mania,
euphoria (31% of patients) and disinhibition (35%
of patients) are common. Few data exist on the
typical symptomatology of frank mania in HD
(83). Raj et al. (84) studied a family with 11 cases
of HD across three generations; five of 11 patients
were also diagnosed with BD. In the proband, the
onset of abnormal movements occurred early (di-
agnosis at age 17 years with a high number of
CAG trinucleotide repeats, consistent with genetic
Mania secondary to brain lesions
anticipation) and coincided with the appearance of
psychiatric symptoms.
Mania in BGC: epidemiology and features. BGC is
a less well-known subcortical neurodegenerative
disease that is strongly associated with mania.
Impressively, 40% of patients with BGC present
with psychiatric symptoms, and among patients
with longstanding BGC, 31% exhibit unipolar
mania or mania alternating with depression (85).
BGC may be idiopathic (Fahr’s disease) or can
occur secondary to hypoparathyroidism, anticon-
vulsant use, or other conditions (86). Calcification
is bilateral and is almost always seen in the globus
pallidus. Other structures involved can include the
caudate, putamen, thalamus, and cerebellum (85,
87). The condition is progressive and may involve
seizures, dementia, and movement disorders (88).
The psychiatric presentation and evidence for
causality vary between case reports. Trautner et al.
(88) reported the case of a patient with BGC,
pathological movements (dystonia and chorea),
and a seven-year course of continuous mania with
disruptive behavior, sexual preoccupation, and
poor executive functioning. The unremitting nat-
ure of mania in this case was consistent with Wool-
ley and colleagues’ characterization of secondary
mania in neurodegenerative disorders as a con-
stant, progressive phenomenon (76) (see above).
Casamassima et al. (89) described a similar case
that ultimately responded to ECT. Other authors
describe patients with new-onset, treatment-
response mania, without motor or cognitive defi-
cits, who upon neuroimaging were determined to
have BGC (90, 91). Consequently, BGC in these
latter patients may have been an incidental finding.
Treatment of mania in neurodegenerative dis-
ease. There are no published studies to guide
pharmacologic management of mania in neurode-
generative conditions. Anecdotal evidence suggests
that psychiatric symptoms generally respond
poorly to treatment (88).
Epilepsy
Epidemiology. Psychiatric disorders are fre-
quently observed in patients with epilepsy, partic-
ularly temporal lobe epilepsy (TLE). Depression
affects 11–44% of people with epilepsy (92), and
mood disorders have been reported in half of
people with TLE (93). Epilepsy-associated mania
is less common and typically presents as postictal
mania or mania after temporal lobectomy
(92). In one case series of 117 consecutive
patients with epilepsy (67% with TLE), 15% met
209
Satzer and Bond
diagnostic criteria for manic/hypomanic episodes
(94).
Features. Based on the abundance of right-sided
structural lesions associated with mania, epilepsy-
associated mania should theoretically present in
one of three ways: (i) ictal mania due to left-sided
epileptiform hyperactivity, (ii) ictal mania due to
right-sided surgical resection for epilepsy, or (iii)
postictal rebound hypoactivity in right-hemisphere
limbic structures. The available data provide some
support for these predictions.
Carran et al. (95) studied a series of patients
with new-onset ictal mania following temporal
lobectomy for epilepsy. Compared to patients with
depression or no mood disorder after surgery,
patients with postoperative mania were more likely
to have shown bilateral preoperative abnormalities
on electroencephalography (EEG; 11 of 16
patients) and undergone right-sided resection (12
of 16 patients). Mania may have resulted from left-
sided persistent seizure foci (as suggested by the
authors) or right-sided surgical lesions. In a review
of 91 cases, Sackeim and colleagues (96) reported
that gelastic epilepsy (ictal pathological laughing)
was three times more likely to be associated with
left-hemisphere than right-hemisphere seizure foci
(68% versus 22%, respectively). Though mania
and pathological laughing are of course distinct,
these data support the above predictions regarding
the laterality of seizure foci.
Contrary to our predictions, in a series of five
patients with postictal mania, all had a seizure
focus in the dominant left hemisphere and exhib-
ited postictal hyper-perfusion either bilaterally or
within the non-dominant right hemisphere (97).
Unfortunately, handedness (i.e., hemispheric dom-
inance) was not specified in these studies, nor in a
separate case report of a patient with mania after
right temporal lobectomy (98).
Treatment. Mood-stabilizing antiepileptic drugs
(e.g., valproate or carbamazepine) are an intuitive
treatment option for epilepsy-associated mania,
but there is little to no empirical evidence to guide
therapy (92). Mood stabilizers and antipsychotics
have been used to treat mania following temporal
lobectomy, though manic episodes may be pro-
tracted (seven of 16 patients in one study had
episodes of duration > six months or recurrent epi-
sodes) (95).
Functional neurosurgery
Epidemiology. Mania has been reported after
stereotactic ablation of subcortical brain structures
210
(99). Deep brain stimulation (DBS), which has lar-
gely replaced ablative procedures, can also produce
mania. New-onset mania or hypomania occurs in
4% of patients undergoing stimulation of the sub-
thalamic nucleus (STN) (100). Mania has also been
observed during DBS of the ventral capsule/ven-
tral striatum (VC/VS) for obsessive-compulsive
disorder (OCD) (101, 102), and five of 10 patients
in one study developed hypomania (103).
Features. Okun et al. (99) described two patients
with Parkinson’s disease who developed post-abla-
tive mania, one following a lesion in the left globus
pallidus pars interna (GPi), and the other follow-
ing lesions in the right GPi and left putamen. In
DBS of the STN, stimulation of the ventromedial
limbic area has been consistently associated with
mania (104–107), while stimulation of the dorsolat-
eral motor area instead may lead to resolution of
manic symptoms (104–106). Interestingly, hypo-
mania is associated with right-sided monopolar
stimulation of VC/VS, but stimulation of the ven-
tral-most contact in the right VC/VS decreases the
risk of hypomania (108). The high prevalence of
manic and hypomanic episodes in DBS of VC/VS
is believed to result from abundant connections
between the nucleus accumbens and the limbic sys-
tem (101, 102).
Treatment. In DBS-associated mania, altering the
stimulation target or parameters frequently leads
to resolution of manic symptoms (101, 104, 105,
107). Antipsychotics and mood stabilizers have
provided benefit in other cases, particularly when
facing a trade-off between psychiatric and motor
symptoms (109), but changing stimulation parame-
ters may still be necessary (102).
Discussion
Clinically distinguishing secondary mania from primary
BD-I
Distinguishing secondary mania from primary
BD-I requires (i) confirming the presence of a cau-
sative brain lesion and (ii) ruling out a primary
BD. Both present clinical challenges. Mania may
be the presenting symptom of a brain lesion, and
the characteristic signs, symptoms, and imaging
findings of the lesion may be subtle or even absent
until it is in an advanced stage. There is little to
suggest that manic symptoms differ in secondary
and primary mania: in large case reviews, all classic
manic symptoms (grandiosity, decreased need for
sleep, pressured speech, flight of ideas, distractibil-
ity, psychomotor agitation, and risky behavior) (1)

were well represented in brain lesion-associated
mania (9, 12, 34). Elevation of mood was often the
presenting symptom (9).
Even when a lesion is detected in a manic
patient, a causal relationship to mania cannot
always be assumed. In fact, the possibility of
reverse causality should be considered—for exam-
ple, BD-I patients’ propensity to engage in risky
behaviors puts them at elevated risk of TBI; and
their high rates of obesity even increase their risk
of stroke (110, 111). In patients with known brain
lesions presenting with mania, ruling out a BD by
excluding prior manic and, especially, hypomanic
episodes (which are by definition of mild severity)
can be surprisingly difficult (112). Finally, even in
patients with known BD, brain lesions may precip-
itate manic episodes or worsen the long-term ill-
ness course.
Clinicians should have a high index of suspicion
for secondary mania, particularly in patients with
the following.
1. Focal or soft neurological signs or symptoms.
2. A manic syndrome with atypical features, such
as visual or olfactory hallucinations; clouding of
consciousness; disorientation; or marked mem-
ory impairment.
3. A first manic episode outside the usual age of
onset for BD-I (15–30 years of age). Some
experts recommend investigating a first mania
after age 40 years for potential secondary causes
(56). Brain lesions are particularly common in
geriatric-first-episode mania; one case series
reported that in people over 65 years, 71% of
those with first manic episodes had a neurologi-
cal disorder, compared to 28% with prior manic
episodes (113).
4. An unusual illness course, such as a single manic
episode with no subsequent mood symptoms;
unremitting mania; or poor response to anti-
manic treatments.
All patients presenting with mania should
undergo a focused neurological history and exami-
nation. Acutely behaviorally disturbed patients
may receive benzodiazepines and/or antipsychotic
medications for behavioral control, and clinicians
should interpret sedation or disorientation accord-
ingly. Significant findings may necessitate brain
imaging and consultation with appropriate special-
ists (psychiatrists, neurologists, and/or neurosur-
geons). Even when a neurologic condition is
present, medications used to treat it may be the
causative agent (e.g., corticosteroids for MS;
L-Dopa for Parkinson’s disease). It is important to
also consider non-neurologic causes of secondary
mania, and to differentiate mania from other
Mania secondary to brain lesions
conditions characterized by changes in affect, cog-
nition, and behavior, such as delirium.
To exclude a diagnosis of BD-I, it is para-
mount to obtain a thorough psychiatric history
to rule out prior manic and hypomanic episodes.
Hypomania and even mild mania are often not
recognized by patients as pathological, creating
challenges in their ascertainment. This difficulty
is compounded by the fact that depressive epi-
sodes predominate in the clinical course of BD-I
for most patients (114). Obtaining a collateral
history from family members and medical
records, and using screening instruments such as
the Mood Disorders Questionnaire and the
Hypomania Checklist-32 (115) increase the prob-
ability of detecting past hypomanias and manias.
In patients with known BD, a clear change in ill-
ness course could be the consequence of organic
pathology. In the end, clinicians should be aware
that a definitive diagnosis of secondary mania
cannot be made for a sizable fraction of patients,
and in such cases clinical decisions must be made
on the balance of probabilities.
Treatment of mania secondary to brain lesions
Theoretically, mania secondary to a brain lesion
will resolve when the causative condition is treated.
In practice, many brain conditions that cause
mania leave permanent damage (e.g., stroke and
TBI), are progressive (e.g., FTD), or cannot always
be treated to remission (e.g., MS). Moreover, the
functional impairment and dangerous behaviors
typical of mania mandate immediate treatment.
Thus, specific interventions for both mania and the
brain lesion are usually required.
Principles for the management of mania should
be applied, as follows.
1. Benzodiazepines and/or antipsychotics are effec-
tive for the emergency management of disinhib-
ited, agitated, or aggressive behavior (116).
Patients with brain lesions may be at higher risk
of extrapyramidal symptoms (EPSs), over-seda-
tion, and ‘paradoxical’ disinhibition, and lower
medication doses and close monitoring are war-
ranted (117). Second-generation antipsychotics
(SGAs) are preferred over first-generation medi-
cations due to their lower propensity for EPS.
2. Mood stabilizers (e.g., lithium, valproate, or
carbamazepine), and SGAs (e.g., risperidone or
olanzapine) are effective in treating core manic
symptoms. Combination treatment with a mood
stabilizer and an SGA is more effective than
monotherapy, and is preferred for severe mania
(118). ECT is effective for severe or treatment-
211
Satzer and Bond
refractory mania, but neurological/neurosurgi-
cal consultation should first be sought to ensure
it is safe in the presence of brain disease (119).
In practice, there are few absolute contra-indica-
tions to ECT.
Unfortunately, there is little information from
randomized controlled trials to guide the pharma-
cotherapy of secondary mania, and decisions
regarding the selection and sequencing of medica-
tions are therefore empirical. As noted in the above
sections, in certain situations the type of brain
lesion may suggest that particular medications
might be more effective, safer, or at least reduce
polytherapy. For example, lithium may be chosen
for mania in the context of stroke as it may aid in
neurological recovery, while antipsychotics should
be avoided as they may impede recovery. Mania in
the context of TLE might be best treated with anti-
convulsants such as valproate, while medications
such as chlorpromazine and clozapine that lower
the seizure threshold should be avoided (120).
The optimal duration of maintenance treatment
to protect against future manic episodes is also
unclear. People with mania secondary to certain
brain lesions are more likely to have a single manic
episode than people with primary BD-I (e.g., 45%
of people with stroke, compared to approximately
5% with BD-I). In such cases, gradual tapering
and discontinuation of anti-manic medications
may be appropriate. Close monitoring for the re-
emergence of manic symptoms during this process
is critical. In contrast, people with other types of
brain lesions, such as TBI and FTD, may experi-
ence chronic manic symptomatology and require
long-term treatment.
Significance of anatomical loci of brain lesions for
understanding the neurobiology of primary bipolar mania
Our knowledge of the functional neuroanatomy of
mania in BD-I is largely derived from neuroimag-
ing studies. To integrate the findings of lesion and
imaging studies, we summarize below the neurobi-
ology of BD-I, as demonstrated by magnetic reso-
nance imaging (MRI).
Brain activity changes associated with BD-I. The
symptomatology of mania suggests that it arises
from abnormal activity in brain circuits involved
in reward processing and emotional response gen-
eration/modulation. This is borne out by numer-
ous functional magnetic resonance imaging
(fMRI) studies; for excellent reviews, see Stra-
kowski et al. (121) and Phillips et al. (122). Among
the most consistently reported findings in people
with BD-I is over-activation of left-hemisphere
212
brain regions important in appetitive/approach
behaviors, including the amygdala and ventrome-
dial PFC, during the anticipation and processing
of reward stimuli (123–125). A second key finding
is bilaterally increased activation of subcortical
emotion-generating brain regions, such as the
amygdala and ventral striatum, accompanied by
decreased activation of regions important to con-
scious (ventrolateral and dorsolateral PFC) and
unconscious (ventromedial PFC and anterior cin-
gulate cortex) emotional regulation (122). These
changes are most pronounced in response to emo-
tionally salient stimuli, particularly positively
valenced stimuli (126, 127). Finally, resting-state
fMRI studies, which examine the coordinated
activity of different brain regions, demonstrate that
the functional connectivity between emotion-gen-
erating and emotion-regulating brain areas is
impaired (128). Interestingly, many of these func-
tional abnormalities are also seen in schizophrenia
(129–132).
Structural brain changes associated with BD-I.
These functional brain changes could result, at
least in part, from abnormalities in brain structure.
Structural brain changes in people with BD-I
include volume reductions and decreased cortical
thickness in frontal and anterior temporal cortical
areas, including the ventral PFC and the anterior
temporal and insular cortices (133–136). Reduced
hippocampal, amygdala, and basal ganglia vol-
umes have also been reported, though somewhat
less consistently. Variability in these findings is
likely related to (i) illness stage, since volume
reductions appear to increase with illness duration
(137), and (ii) pharmacotherapy, since they tend to
reverse with mood stabilizer treatment, particu-
larly with lithium (138).
White matter changes are also a well-character-
ized feature of BD-I. T2-hyperintense foci are fre-
quently seen, particularly in deep white matter
(139, 140). Frontal and temporal white matter vol-
ume reductions are prominent in early-stage
patients, suggesting that they may be important in
the genesis of BD-I (141). Moreover, diffusion
MRI has identified evidence of axonal damage in
frontal and temporal white matter (122, 142).
Abnormal tracts include the anterior corpus callo-
sum, anterior cingulum, uncinate fasciculus, and
superior longitudinal fasciculus, all of which link
important emotion-generating and emotion-regu-
lating brain areas (143–145).
Whereas reward-processing abnormalities are
most prominent in the left hemisphere, structural
brain changes appear to be more prominent in the
right. This is best demonstrated by meta-analyses

of imaging studies, which are able to identify the
most consistently abnormal areas. A meta-analysis
of voxel-based MRI studies found a single cluster
of reduced right-hemisphere gray matter volume
that encompassed portions of the ventrolateral
PFC, temporal cortex, insula, and claustrum (133).
Interestingly, several other brain regions including
the bilateral PFC and anterior cingulate cortex
showed significant heterogeneity between studies,
indicating that they may be relevant to certain ill-
ness stages or subtypes of BD-I. A second meta-
analysis of diffusion tensor imaging (DTI) studies
reported two clusters of decreased right-hemi-
sphere fractional anisotropy, one near the parahip-
pocampal gyrus and the second near the ventral
portion of the corpus callosum (144). These clus-
ters were crossed by white matter tracts that con-
nect limbic brain areas, including the superior
longitudinal fasciculus, the inferior fronto-occipital
fasciculus, and the inferior longitudinal fasciculus.
Interpretation of MRI data. In summary, MRI
studies in BD-I suggest a model in which height-
ened emotion- and reward-related limbic brain
activity is inadequately constrained by underactive
prefrontal regulatory regions. The most consistent
abnormalities include (i) hyperactivity of left-sided
reward-processing regions and (ii) decreased size
and integrity of right-sided limbic structures and
connecting tracts. One parsimonious interpretation
of these findings is that mania is characterized by
an abnormal shift in reward-processing activity to
the left hemisphere, as a result of left-sided overac-
tivity, right-sided underactivity, or both. This
interpretation depends upon an association
between right-sided volume reductions and (i)
functional disconnectivity in the right hemisphere
and/or (ii) decreased right-sided reward-processing
activity. Whether this association exists is currently
unknown. The relationship cannot be assumed,
especially since volume reductions in some brain
regions in BD-I (notably the ventral anterior cin-
gulate cortex) are associated with increased activity
during mania (146).
Role of lesion studies in understanding the patho-
physiology of mania and BD-I. Lesion studies have
received less attention than imaging studies in elu-
cidating the pathophysiology of mania. Lesion
studies are not without their drawbacks; for exam-
ple, lesions often expand beyond the boundaries of
the anatomic regions of interest, and can even
affect the functioning of distant brain regions via
mass effects and disconnection syndromes (147).
Moreover, although the lesions we have reviewed
here were associated with manic syndromes, it is
Mania secondary to brain lesions
unlikely that they precisely replicate the underlying
neurobiology of BD-I, making comparisons
between the two imperfect. Nonetheless, lesion
studies provide information about mania that
imaging studies cannot. In particular, lesion stud-
ies can identify regions necessary for particular
functions, while imaging studies can only provide
data regarding relative brain activity (148). The
two research modalities are thus complementary,
and cases of secondary mania can help advance
our understanding of the biology of primary
mania.
Brain structures involved in BD-I. The evidence
from lesion studies largely supports the conclu-
sions drawn from imaging studies, in showing that
mania is most common with lesions involving fron-
tal, temporal, and subcortical limbic brain regions
—particularly the PFC, medial temporal lobe,
basal ganglia, and connecting pathways (121, 122,
133). Right-hemisphere structural lesions appear
to be over-represented. In contrast, left-sided later-
ality appears to predominate for excitatory lesions
such as epileptogenic foci, particularly temporal
lobe epileptogenic foci. Lesions affecting other
structures (e.g., the brainstem and cerebellum) are
less frequent causes of secondary mania, and may
produce similar pathology via output to the basal
ganglia (20, 21, 53, 55, 62, 149, 150). Table 2 pro-
vides a summary of large studies that relate sec-
ondary mania to specific lesion anatomy. Causality
between lesions and mania is most clearly demon-
strable when the lesions are acute, discrete, and cir-
cumscribed (e.g., stroke and neoplasms). It is
understandably more difficult to demonstrate in
chronic or multifocal lesions (e.g., TBI and neu-
rodegenerative disorders).
Lesion studies may also expand our knowledge
of the neurobiology of BD-I by providing informa-
tion about the nature of structural lesions that
imaging studies cannot. It is tempting to speculate
that the right-hemisphere reductions in limbic
brain volumes and white matter integrity detected
by imaging studies in BD-I are associated with
reduced activity and/or disconnectivity in the
affected regions. This would in turn suggest that a
core abnormality in primary mania is a shift
of emotion and reward processing to the left
hemisphere, due to a combined effect of left-sided
overactivity and right-sided underactivity. How-
ever, for this to be true, the right-hemisphere imag-
ing findings would have to be associated with
reduced activity, which has not been demonstrated.
The contribution of lesion studies is in demonstrat-
ing that the structural brain lesions most reliably
associated with secondary mania (namely, strokes
213
Satzer and Bond

Table 2. Summary of large studies examining the relationship between mania (or related symptoms) and specific lesion anatomy

Disease Study Lesion Lesion

Study state type Patients laterality anatomy

Santos et al. 2011 Stroke Systematic 74 with mania 77% right Not studied
(9) review
Jorge et al. 1993 TBI Case series 66 with TBI No significant Basotemporal lesions
(34) (six with mania) difference most common
Present report Brain tumor Case series 23 with mania 75% right Frontal, temporal,
or limbic in 81%
Liu et al. 2004 FTD Cohort study 51 with FTD Disinhibition associated with decreased volume
(78) (37 with disinhibition) in right amygdala, right ventromedial PFC, and
right anterior temporal cortex
Carran et al. 2003 Epilepsy Case series 16 with mania after 75% right-sided Temporal lobe
(95) temporal lobectomy resection
Sackeim et al. 1982 Epilepsy Case series 91 with gelastic 40% left seizure Not studied
(96) epilepsy focus (versus 19%
right)
Widge et al. 2015 Neurosurgery Case series 20 with VC/VS Hypomania Stimulation through right
(108) DBS associated with right ventral-most contact was
(nine with monopolar negatively associated with
hypomania) stimulation hypomania
Robinson et al. Multiple etiologies Cohort study 17 with mania and 71% right (versus 6% Most often basal temporal
1988 (12) stroke/TBI/tumor left) lobe, ventral PFC,
thalamus, or caudate

FTD = frontotemporal dementia; PFC = prefrontal cortex; TBI = traumatic brain injury; VC/VS DBS = deep brain stimulation of the ventral
capsule/ventral striatum.

and brain tumors) are clearly associated with
hypofunctionality, thus providing support for this
hypothesis. It may be that reduced right-hemi-
sphere activity in primary mania is relatively sub-
tle, hard to detect with functional imaging, and
only able to cause mania in conjunction with left-
sided overactivity. In contrast, the gross and often
relatively sudden underactivity resulting from
strokes, brain tumors, and other lesions may shift
left right activity balance enough to cause mania
on its own, without left-sided involvement.
Additional information germane to the patho-
physiology of primary mania can also be gleaned
from lesion studies. For example, right-sided corti-
cal and subcortical lesions appear to produce simi-
lar physiological changes but different psychiatric
phenotypes. Starkstein and colleagues (14) studied
a cohort of patients with mania secondary to a
number of different brain lesions, including stroke,
head trauma, and tumors. Patients were divided by
lesion location: right cortical (ventral PFC) or
right subcortical (subfrontal white matter, anterior
limb of the internal capsule, or caudate). Positron
emission tomography (PET) in patients with
subcortical infarcts demonstrated hypoactivity of
the right ventrolateral PFC (patients with ventral
PFC infarcts were assumed to also have ventral
PFC hypoactivity). Starkstein et al. (15) subse-
quently reported that right cortical (predominantly
ventromedial PFC and basotemporal cortex)
lesions were associated with unipolar mania, while
214
right subcortical (primarily caudate and thalamus)
lesions yielded alternating mania and depression.
Lesion symptom causality was supported by the
close temporal relationship between lesion and
mood disorder onset; depression typically arose
within 1 week after lesion appearance, and the
median onset for mania was 4.5 weeks (range:
2–26 weeks).
These reports are consistent with the theory that
mania arises when limbic structures escape from
prefrontal regulation, and furthermore suggest pre-
frontal dependence upon the basal ganglia. In
patients with secondary manic-depressive illness,
manic episodes after initial acute depression pre-
sumably result from latent hypoactivity in connec-
tions between the basal ganglia and ventral PFC
(15). Subcortical lesions have been associated with
depression—though interestingly this finding pri-
marily applies to left-sided lesions (151)—and may
produce acute depression via different mechanisms
than those discussed in this review.
Laterality and BD-I. In both primary BD-I and
secondary mania, the balance of brain activity
appears to be shifted towards the left hemisphere,
due to left-sided hyperactivity (e.g., left-sided
epileptogenic foci) and/or right-sided hypoactivity
(e.g., right-sided infarcts). Conversely, a number of
studies show that secondary depression is associ-
ated with destructive lesions of the left hemisphere
(96, 151, 152). Of note, the association between

relative left-sided hyperactivity and secondary
mania is variable; multiple reports of mania with
left-sided/dominant-hemispheric lesions or right-
sided seizure foci are discussed above. This is to be
expected, since BD-I is almost certainly a heteroge-
neous illness, and even the most consistent imaging
findings of left-sided limbic hyperactivity and
right-sided structural lesions will not explain the
pathophysiology of mania in all patients.
The reasons for this functional asymmetry and
its phenotypic consequences are unclear. One pos-
sibility is that right- and left-sided catecholamine
pathways differ from one another. Robinson (153)
found that rats with right middle cerebral artery
(MCA) infarcts exhibited behavioral hyperactivity
and reduced norepinephrine and dopamine levels,
while rats with left MCA infarcts did not. In the
valence model of emotion, positive and negative
emotions arise from the left and right hemispheres,
respectively (154). While this theory may be over-
generalized, it appears to hold true for specific
structures—particularly the amygdala (155). Pre-
frontal and subcortical imbalance favoring the left
side may therefore result in the euphoric symptoms
present in mania.
Surgical treatment of BD-I: past and future
Operative interventions for BD-I predate knowl-
edge of the functional anatomy of mania. For
example, prefrontal leukotomy gained popularity
in the 1930s and 1940s (156) and was reported to
reduce mania (157), but severe adverse effects (ex-
ecutive dysfunction, epilepsy, and death) greatly
outweighed the benefits (158). More refined, effec-
tive (159) stereotactic procedures were subse-
quently developed, but pharmacotherapy has been
the mainstay treatment for BD-I for decades (156).
Neuroanatomic theories of mania, bolstered by
information lesion studies, suggest rational, tar-
geted approaches for the surgical treatment of
BD-I.
Advances in neurobiology and engineering have
led to a recent psychosurgical rebirth. DBS has
shown benefit in OCD (103, 160) and is being
investigated in both unipolar and bipolar depres-
sion (161, 162). The subgenual cingulate is a lead-
ing target in DBS for major depressive disorder
(161), and DBS of the subgenual cingulate has
shown efficacy in BD-II depression (162). VC/VS
has also been proposed as a DBS target in bipolar
depression (163), and one such trial is currently
recruiting participants (164). There is concern that
DBS for bipolar depression could induce mania,
given (i) case reports of stimulation-induced mania
(outlined above), (ii) the risk of antidepressant-
Mania secondary to brain lesions
induced mania in BD (165), and (iii) evidence of
hyperactivity in the subgenual cingulate during
mania in BD-I (146). However, researchers study-
ing a small cohort of patients undergoing DBS for
bipolar depression reported no manic or hypo-
manic episodes and no change in the Young Mania
Rating Scale score (162).
DBS for bipolar mania is not currently under
investigation. Compared to depression, mania is
more easily treated with pharmacotherapy, and
arguably constitutes a smaller portion of the dis-
ease burden. Nevertheless, the possibility of using
DBS to treat manic symptoms has been raised
(163). As the neuroanatomy of mania is elucidated,
patients with refractory mania may become candi-
dates for DBS research trials.
Conclusions
Mania is a psychiatric emergency seen most fre-
quently in BD-I and schizoaffective disorder, but
brain lesions can also produce secondary mania.
Acute brain insults, chronic neurological disorders,
and neurosurgical interventions have all been associ-
ated with mania. Secondary mania should be consid-
ered particularly in patients with a first manic
episode after age 40 years, mania with atypical symp-
toms (e.g., visual or olfactory hallucinations) or lon-
gitudinal course (e.g., single manic episode or
refractory mania), or neurological symptoms.
The treatment of secondary mania is similar to
the treatment of mania in BD-I, with some excep-
tions; some mood stabilizers have unacceptable
side effects (e.g., diminished brain recovery fol-
lowing stroke due to antipsychotics; seizures due
to lithium), and mania is poorly responsive to
treatment in some conditions, especially neurode-
generative disorders. Advances in understanding
the biology of mania may facilitate the develop-
ment of novel mood-stabilizing therapies such as
DBS.
Lesion studies support and complement neu-
roimaging studies in BD-I. Both support the the-
ory that mania arises from insufficient prefrontal
regulation of limbic structures, and hyperactivity
of the limbic system within the left (or dominant)
hemisphere. However, more research is necessary
to understand how exactly these patterns lead to
the elated, expansive, and irritable symptoms of
mania.
Disclosures
DJB has received research support from: the Canadian Insti-
tutes of Health Research (CIHR), the UBC Institute of
Mental Health/Coast Capital Depression Research Fund,
215
Satzer and Bond
and Pfizer; and has received speaking fees from or partici-
pated on advisory boards for the Canadian Network for
Mood and Anxiety Treatments (CANMAT), the Canadian
Psychiatric Association, Pfizer, Sunovion, BMS, Otsuka,
AstraZeneca, Janssen-Ortho, and Myriad. DS has no con-
flicts of interest to report.
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