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old age. Furthermore, the late peak in hospital admissions may represent a group
who are suffering from neurologic comorbidity and require hospitalization
because of the severity of their illness or associated vascular risk factors.
Certainly more work examining age of onset is needed.
In approximately half of index cases of mania in late life, the first affective episode
is a depression which is similar to the proportion in mixed-age populations (Stone,
1989; Snowdon, 1991; Broadhead and Jacoby, 1990; Shulman et al., 1992). However
what distinguishes the elderly bipolar patient in terms of clinical course is the very
long latency (on average 15 years) before mania becomes manifest (Shulman and
Post, 1980). Furthermore, a delay of at least 25 years (ranging up to 47 years)
between first depression and first mania occurs in about one-quarter of these
patients. In further defining the clinical course, it is noteworthy that following a
first episode of depression, approximately half of the cohort went on to develop
three distinct depressive episodes before experiencing their first manic episode
(Shulman and Post, 1980; Broadhead and Jacoby, 1990; Snowdon, 1991). This
prolonged latency followed by a ˜˜conversion™™ to bipolarity after many years of an
apparently unipolar diagnosis raises the notion of secondary mania associated with
neurologic comorbidity as an important aspect of late-life bipolar disorders.
There is a small group of elderly bipolar patients whose clinical course is
characterized by manic episodes only and who meet the criteria for unipolar
mania (Shulman and Tohen, 1994). In this latter study, subjects were required
to experience at least three distinct manic episodes without evidence of a major
depression for a minimum period of 10 years from the time of the first manic
admission. Of considerable interest is the difference in age of onset in this
subgroup of unipolar manic patients. Here the age of onset was significantly
lower at 41 years compared to a mean of 65 years for the bipolar elderly manics.
Thus, the unipolar manic patients were among the very few elderly bipolar patients
whose illness began early in life (Shulman and Tohen, 1994). This raises possible
differences in pathogenesis and genetic vulnerability.
Mortality outcome has been reported in two studies with a mean of 6 years™
follow-up data (Dhingra and Rabins, 1991; Shulman et al., 1992). In the study by
Dhingra and Rabins (1991), approximately one-third of the original cohort had
255 Atypical features of bipolarity in old age


died at follow-up. Shulman et al. (1992) found a significant difference in mortality
in an elderly manic group compared to an age- and sex-matched group of unipolar
depressives. At the end of the 6-year mean follow-up period, 25 of the 50 manic
patients were dead compared with only 20% of the depressed patients. After 5
years of follow-up, the probability of remaining alive was 90% for those with
unipolar major depression and only 65% for patients with mania. At 10-year
follow-up, the probability of remaining alive was 75% for the depressives and
only 30% for the manic group. It should be noted that the data for the study were
for hospitalized manic patients and studies of mortality outcome in outpatients
are now needed.

Neurologic comorbidity
Retrospective cohort studies of mania in late life have established a very clear
association between bipolarity in old age and a heterogeneous group of neurological
disorders (Shulman and Post, 1980; Shulman et al., 1992; Shulman and Singh,
1999). Even when compared to age-and sex-matched cases of depression where
the prevalence of neurologic disorders was 8%, the elderly bipolar patients had a
significantly higher rate of heterogeneous neurologic comorbidity (36%) (Shulman
et al., 1992). Within the elderly manic subgroup, a very late onset of mania was even
more likely to be associated with neurologic disease (71%) compared to those with
multiple previous episodes (28%) (Tohen et al., 1994). Thus, very-late-onset mania
is strongly associated with neurologic comorbidity as well as an increased mortality
most likely related to the presence of cerebrovascular disease. This was true in 10 of
14 patients whose first affective episode was manic in nature. Furthermore, com-
prehensive reviews of mixed-age populations with ˜˜secondary mania™™ show a variety
of both common and exotic neurologic conditions (Strakowski et al., 1994; Verdoux
and Bourgeois, 1995). However, in both cohorts, cerebrovascular disease predomi-
nates in terms of its association with mania, especially right-sided lesions involving
the orbital-frontal and temporal cortices. This was most pronounced in those elderly
bipolars with very-late-onset mania (Tohen et al., 1994).
The evidence for localization in geriatric mania is based primarily on individual
case reports and case series (Starkstein et al., 1990). However, Braun et al. (1999)
pooled all case reports involving focal unilateral cortical lesions and confirmed the
trend for right-sided lesions to produce manic syndromes while left-sided lesions
were associated with depressive symptomatology. Similar to other reports, the
brain lesions described in the literature were dominated by cerebrovascular
pathology and in particular cerebral infarction.
In neuroimaging studies, two areas of research have strengthened the associa-
tion between cerebrovascular disease and manic syndromes (McDonald et al.,
1999). The first is the finding of an increase in subcortical hyperintensities on
256 K. I. Shulman


magnetic resonance imaging scans. These hyperintensities are associated with
hypertension, diabetes mellitus, and arteriosclerotic heart disease. The second
major neuroimaging finding, led by Japanese investigators (Kobayashi et al.,
1991; Fujikawa et al., 1995), is the presence of silent cerebral infarctions. These
investigators have shown a progressive age-related increase in silent cerebral
infarctions ranging from 6% in middle-aged individuals to greater than 20% in
an elderly subgroup. Compared to late-onset depression and early-onset mood
disorder, the highest frequency of silent cerebral infarctions occurs in the late-
onset manic subgroup (Fujikawa et al., 1995). Conceptually, these individuals fall
into the category of secondary mania with a relatively lower incidence of family
history in first-degree relatives and a higher prevalence of cerebrovascular risk
factors.
Recent volumetric studies of bipolar patients show a trend towards diffuse
cerebral atrophy (Steffens and Krishnan, 1998; Young et al., 1999). These studies
need replication and further elaboration of their significance.

Cognitive impairment
One of the unique elements of studying an elderly cohort is the expected higher
prevalence of cognitive dysfunction that may affect outcome and potentially
treatment response. In preliminary studies of manic syndromes in late life, there
has been a consistent association of cognitive dysfunction. Berrios and Bakshi
(1991) found elderly manic patients to be more cognitively impaired and to have
scored higher on the Hachinski Scale, reflecting cerebrovascular pathology, when
compared to a matched group of elderly depressives. Furthermore, Dhingra and
Rabins (1991) reported scores of less than 24 on the Mini-Mental State Examination
in almost one-third of their elderly manic patients during a 5“7-year follow-up. An
earlier suggestion that the increased incidence of first admission rates for mania at
the extremes of old age might be due to the onset of a dementing illness (Spicer
et al., 1973) has not been substantiated by the few outcome studies available
(Stone, 1989; Shulman et al., 1992). However this issue still requires clarification
and long-term follow-up, including documentation of cognitive function. This is
especially true since the finding by Alexopoulos et al. (1993) that patients with
depressive pseudodementia, if followed for more than 3 years, will develop an
irreversible dementia.
Preliminary studies have suggested that cognitive impairment will affect treat-
ment response (Wylie et al., 1999; R. C. Young, personal communication, 2002).
Recent interest has focused on executive performance in elderly bipolars and initial
findings on a variety of tests of executive and frontal function show impairment in
elderly manic patients compared to controls (R. C. Young, personal communica-
tion, 2002).
257 Atypical features of bipolarity in old age


Nosologic confusion
Depending on whether one is conversant with the neurological or psychiatric
literature, terms such as ˜˜disinhibition syndrome™™ may be replaced with the
concept of ˜˜secondary mania.™™ The actual description of these two syndromes
however is virtually identical (Shulman, 1997). In particular, it is the high rate of
neurologic comorbidity that causes difficulty for categorization of the hetero-
geneous manic syndromes seen in old age. For example, the Diagnostic and
Statistical Manual of Mental Disorders, 4th edn (DSM-IV: American Psychiatric
Association, 1994) established a category of ˜˜mood disorder due to a general
medical condition™™ (293.83) indicating that ˜˜the disturbance is the direct physio-
logic consequence of a general medical condition.™™ However, in an elderly sub-
population, even when there is a close temporal association, it is difficult to
determine whether the medical or neurological comorbidity is a ˜˜direct physio-
logic consequence,™™ simply an associated finding, or just a precipitant. Thus, the
assumption of an etiological relationship is highly questionable.
Krauthammer and Klerman (1978) proposed the notion of secondary mania
and posit a close temporal relationship between the medical/neurological condi-
tion and the manic syndrome. They stipulated that there should be no family
history and no prior history of mood disorder and took pains to distinguish
secondary mania from the syndrome of delirium.
Most recently, investigators have proposed a concept of vascular mood disorder
including both vascular depression and vascular mania (Krishnan and McDonald,
1995; Alexopoulos et al., 1997; Steffens and Krishnan, 1998). The original notion
of ˜vascular depression™ rests on a number of clinical observations and imaging
findings, including a higher prevalence of cognitive dysfunction, increased cere-
bral atrophy and hyperintensities in late-onset depression (Alexopoulos et al.,
1997). This subtype of depression was also associated with greater functional
disability, higher morbidity and mortality, as well as a lower genetic predisposition
compared to early-onset patients. Using a similar template, Steffens and Krishnan
(1998) detailed the criteria for a vascular mania subtype (Table 11.1).


Proposed subtypes
Based on the available literature, Shulman and Herrmann (2002) have proposed
four subtypes that may have heuristic value for further research.
(1) Primary bipolar disorder: this subtype should be used for those early-onset
patients who continue to show mood disorder into old age. Despite the fact
that relatively few of these individuals appear in studies of hospitalized elderly
bipolar patients, it is likely that community and outpatient samples of elderly
bipolar patients will reveal a higher proportion of the subtype.
258 K. I. Shulman



Table 11.1 Proposed criteria for vascular mania subtype specifier

A. Mania occurring in the context of clinical and/or neuroimaging evidence of
cerebrovascular disease or neuropsychological impairment
B1. Clinical manifestations may include history of stroke or transient ischemic attacks, or
focal neurological signs or symptoms (e.g., exaggeration of deep tendon reflexes, extensor
plantar response, pseudobulbar palsy, gait disturbance, weakness of an extremity)
B2. Neuroimaging findings may include white- or gray-matter hyperintensities (Fazekas et al.,
1998 criteria >2 ; or lesion >5 mm in diameter and irregular in shape), confluent white-
matter lesions, or cortical or subcortical infarcts
B3. Cognitive impairment manifested by disturbance of executive function (e.g., planning,
organizing, sequencing, abstracting), memory, or speed of processing of information
The diagnosis is supported by the following features:
1. Mania onset after 50 years of age or change in the course of mood disorder after the onset of
vascular disease in patients with onset before 50 years of age
2. Lack of family history of mood disorders
3. Marked disability in instrumental or self-maintenance activities of daily living

Reprinted with permission from Biological Psychiatry, 43, Steffens, D. C. and Krishnan, K. R. R.
Structural neuroimaging and mood disorders. Recent findings, implications for classification,
and future directions, 705“12, copyright 1990, with permission from Society of Biological
Psychiatry.
Specify vascular subtype (can be applied to the current or most recent manic episode in bipolar
disorder) if A and B1 or B2 or B3.



(2) Latent bipolar disorder: this subgroup is related to elderly bipolars whose
onset began in middle age as a first episode of depression but who ˜˜converted™™
to mania much later in life, often after a prolonged latency and repeated
depressive episodes. In this subgroup, it is postulated that cerebral factors may
be responsible for the ˜˜conversion™™ from a unipolar depressive pattern to that
of bipolarity.
(3) Secondary mania (disinhibition syndromes): this is largely a late-onset sub-
type without prior history of mood disorder and a lower but still significant
familial predisposition. It is necessary to find a neurological or other systemic
medical disorder that is associated with the manic syndrome. The proposed
vascular mania subtype would fall into this subgroup.
(4) Unipolar mania: this is a much smaller but potentially heuristically valuable
subgroup who have a course of manic-only episodes, generally of early onset
and persisting over a prolonged period of time. Their similarity to patients
with chronic frontal disinhibition is of interest but requires further
investigation.
259 Atypical features of bipolarity in old age



Atypical treatment issues
While pharmacokinetic and pharmacodynamic factors dictate a significant alteration
in dosage, the general approach to treatment of bipolarity is not fundamentally
different in an elderly population (Shulman and Herrmann, 2002). The narrow
therapeutic range for pharmacological therapies in old age is an important considera-
tion in ongoing management. Some interesting questions remain with respect to the
atypical features of bipolar disorder in the elderly. First and foremost is the question
of the impact of secondary mania on treatment and outcome. Will patients with
frank neurologic lesions and a diagnosis of secondary mania respond in a way similar
to the so-called primary bipolar subgroup? Further, how does cognitive dysfunction
affect treatment outcome? Because of the narrow therapeutic range, do combination
therapies in old age have a greater role in order to accommodate for limiting side-
effects of individual drugs such as lithium carbonate and atypical neuroleptic agents
such as olanzapine and risperidone? Can we use lower dosages of these drugs in
combination, thereby limiting side-effects but maintaining effectiveness?
Finally, it has been proposed that the vascular subtype of mania may have specific
implications for treatment. Instead of the usual mood stabilizers such as lithium,
divalproex, and the atypical neuroleptic olanzapine, drugs that target cerebrovascu-
lar disease may be more appropriate for this subgroup. The calcium channel blocker
nimodipine was used as an augmenting agent to standard antidepressant therapy in a
group of patients suffering from ˜˜vascular depression™™ (Taragano et al., 2001). These
researchers were able to show a significant decrease in depressive symptoms and a
low rate of recurrence with this agent used to treat cerebrovascular disease. Whether
this effect can be translated to vascular mania remains to be determined.
Some specific geriatric issues do influence the use of lithium carbonate in the
elderly. First and foremost is the fact that lithium is excreted exclusively by the
kidneys (Hardy et al., 1997) and aging effects lead to a very significantly altered
elimination half-life. Combined with a decrease in the volume of distribution,
marked reductions in lithium dosage are necessary.
From a pharmacodynamic viewpoint, sensitivity also appears to be increased in
old age (Shulman and Herrmann, 1999). It is clear that adverse reactions and
lithium toxicity at so-called normal adult serum levels are a common problem
(Roose et al., 1979; Smith and Helms, 1982; Murray et al., 1983;). There is still a
lack of clear guidelines regarding maintenance serum levels for the elderly,
although by and large the figure of 0.5 mmol/l has been most commonly used as
a target (Shulman et al., 1987; Shulman and Herrmann, 2002).
Because the elderly are more likely to consume other drugs because of comorbid
medical conditions, drug interactions with lithium carbonate remain a special
concern. In particular, the diuretics which can decrease lithium clearance and
260 K. I. Shulman


significantly increase serum lithium levels are a potential hazard. Other medica-
tions that have been implicated in raising serum lithium levels include the angio-
tensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs
such as indometacin (Shulman and Herrmann, 1999).
Case reports suggest that divalproex is still a fairly safe medication in the elderly,
although there have been no systematic studies in this subpopulation. There is
some evidence that it is surpassing lithium as a first-line mood stabilizer treatment
in old age, despite the fact that there are few hard data to support this change in
prescription pattern (Dinan, 2002).
Isolated case reports suggest only limited experience with other mood-
stabilizing agents such as gabapentin, lamotrigine, olanzapine, risperidone,
and quetiapine in the elderly (Shulman et al., 1997; Jeste et al., 1999; Tohen
et al., 1999).



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