INT'L. J. PSYCHIATRY IN MEDICINE, Vol. 22(4) 377-395,1992

THE EXPRESSION OF BIPOLAR AFFECTIVE DISORDERS IN BRAIN INJURED PATIENTS

ALEXANDER S. ZWIL, M.D. Jefferson Medical College and Thomas Jefferson Medical University Hospital, Philadelphia THOMAS W. McALLISTER, M.D. Dartmouth Medical School and The New Hampshire Hospital, Concord ERIC RAIMO, B.A. Dartmouth Medical School, New Hampshire

ABSTRACT

Objective: A prospective study was designed to investigate the varied presentations of major affective disorders in patients with organic brain disease. Method: Patients admitted to our newopsychiatry service, with affective and behavioral disturbances, and known neurological disorders, were classified, on phenomenological grounds, into the following groups: 1) elated mania; 2) irritable mania; 3) affective lability with periods of irritability, but without other symptoms pathognomonic for mania; and 4) intermittent psychosis with absent or ambiguous mood changes. Results: A majority of patients in all four groups responded to pharmacotherapy with anti-cycling agents. Conclusions: It is proposed that these groups represent different expressions of mania in brain injured persons, and that these expressions range through a spectrum of phenomenology, included elated mania, irritable mania, episodic psychosis and explosive organic personality disorder. The DSM-111-R classification of these disorders, and approaches to their clinical management, are discussed. (/nt%J. Psychiatry in Medicine 22:377-395, 1992)

Key Words: affective disorders, affective symptoms, bipolar disorder, manic disorder, organic mental disorders, brain injuries, head injuries, delusions, aggression, organic mood disorders, cycloid psychoses, episodic dyscontrol 377

0 1992,Baywood Publishing Co., Inc.

doi: 10.2190/J71J-FTML-JY1E-RKKG http://baywood.com

378 / NVIL, McAUlSTER AND RAlMO

Patients with organic brain disease and affective disturbances are frequently encountered by psychiatrists on emergency room and general hospital consultations, crisis center evaluations, and psychiatric in-patient units. They present difficult diagnostic and management dilemmas, since they often differ significantly from patients with idiopathic psychiatric disorders in their presentation and response to treatment, and may be extremely sensitive to medication side effects. While some of these disorders may resemble idiopathic psychiatric diseases phenomenologically [l],organic brain lesions may alter or mask the signs and symptoms of affective disease in some patients, making phenomenological diagnosis difficult [2]. Symptoms of irritability, pathological elation, depression, psychosis and behavioral dyscontrol are very common in patients, having a wide variety of neurological lesions associated with psychiatric disturbances, referred to our neuropsychiatry service. In many cases, it has been difficult to separate these syndromes into discrete psychopathological entities, due to the overlap in symptomatology, and to the ambiguity of the DSM-111-R [3] classification of organic disorders. Furthermore, although many different psychotropicagents have been reported to be useful in controlling a variety of behavioral symptoms in neurologically impaired patients, it is difficult to predict which specific behaviors will respond to specific agents [4]. Since the pathophysiology underlying these behavioral changes is not well understood, and rational, specific pharmacotherapy is usually not possible, a reasonable treatment approach is to conduct a series of empirical trials with specific pharmacological agents [5]. In the authors’ prior experience, many neurologically impaired patients displaying symptoms of elation, irritability, episodic aggression or behavioral dyscontrol, and periodic or recurring psychosis, had responded to treatment with anticycling medications, chiefly lithium carbonate, carbamazepine and low-dose neuroleptics. This observation led us to hypothesize that these syndromesmay represent a spectrum of the expression of bipolar affective disease in brain-injured persons, and to undertake a prospective, uncontrolled study of the effectiveness of anti-cycling medications in such patients. Initially, a review of the literature was conducted to identify specific reported syndromeswhich may represent the varied expressions of cyclic affective disease in neurological1y-impaired patients. Symptoms of depression and mania have been reported in association with neurological disorders for many years. Krauthammer and Klerman defined the concept of mania secondary to medical and neurological disease, and reviewed the cases reported in the literature up to that time [6]. They proposed that the manic syndrome may have multiple causes, and would eventually be found to encompass a continuum of psychopathological syndromes. Stasiek and &tin updated this review to 1985 [7]. Larson and Richelson again reviewed the literature between 1965 and 1987, and published a very exhaustive list of cases and reported etiologies [8]. Yassa et al. reported a high incidence of neurological features in patients with late onset mania (after the age of 50) [9]. Shukla et al. pointed out

BIPOLAR AFFECTIVE DISORDERS / 379

that the neurological antecedents of manic syndromes often went unnoticed by psychiatrists [lo]. Cummings and Mendez [ll] and Cummings [12] suggested that secondary mania occurred most frequently in association with injury to limbic-connected right-hemisphericstructures. Starkstein, Robinson and their colleagues [13-181 reported extensively upon patients with mania secondary to focal brain disease, and concluded that secondary mania occurred most frequently in association with right-hemisphericlesions, especially those involving injury to the orbitofrontal and basotemporal cortical areas, basal ganglia and thalamus, specifically implicating dysfunction in the right basotemporal cortex [17,18]. They [13] and Shukla et al. [19] pointed out that many patients with secondary mania also had episodes of depression, i.e., had bipolar mood disturbances. Silver and Yudofsky reviewed the literature on episodic aggression and behavioral dyscontrol associated with brain injury, and reported that it frequently occurred in conjunction with mood lability, irritability, intrusiveness, boisterousness, impulsivity, distractibility and manic states in patients with frontal lobe injury [20]. This syndrome, frequently referred to as Episodic Dyscontrol, is classified as Organic Personality Disorder-Explosive Type (OPD-ET) in DSM-III-R [3,21,22]. Starkstein et al. reported an association between secondary mania and injury to right hemisphere structures with strong connections to the frontal lobes, and pointed out the similarities between irritable mania and the “pseudopsychopathic syndrome” resulting from injury to the orbitofrontal cortex [15]. Shukla et al. reported that irritability and assaultiveness were more characteristic of their patients with secondary mania than was elation [19]. Convulsive [23] and pharmacological [5, 241 therapies effective in the treatment of mania and bipolar mood cycling have also been reported to ameliorate the symptoms of OPD-ET. Since Kraepelin defined the distinction between schizophrenia (dementia praecox) and bipolar affective disease (manic-depressive insanity), it has been realized that a group of patients existed that did not fit entirely within either category, or had psychopathological features characteristic of both. The classification of these disorders has remained controversial since that time. A variety of terms, including cycloid psychosis, episodic psychosis, atypical psychosis, and others, have been used for many years to describe a group of patients who display findings resembling the positive symptoms of schizophrenia during the active phases of their psychoses, but who follow a recurring and remitting course, with complete recovery between episodes, and have a relatively good prognosis [25-301. In DSM-III-R, many of these patients are classified as having Schizoaffective Disorder or Schizophreniform Disorder, although neither of these categories is satisfactory to encompass the variety of syndromes which have been described [28,31,32]. Although this may be a heterogeneous group of disorders, it has been suggested that at least some of them represent variants of affective disorders, in which the pathognomonic mood changes are overshadowed or altered by prominent thought disorder or motoric symptoms [27,28,33-381. Some

380 / ZWIL, McALLlSTERAND RAlMO

patients with cycloid psychoses have been reported to respond to electroconvulsive therapy (ECT) and to lithium prophylaxis [28]. Delusional and hallucinatory symptoms, without prominent mood disturbances, have also been reported to occur in association with focal lesions in limbic-connected structures, especially in the right hemisphere [ l , 121, suggesting a pathophysiological similarity between recurring psychoses and secondary mania in brain-injured patients. We present here a series of patients with neurological disease and concurrent affective or behavioral disturbances, including euphoric and irritable mood changes, episodic aggression, and intermittent psychosis, which suggest diagnostic and therapeutic similarities between the DSM-III-R categories of Organic Mood Disorder-Manic or -Mixed, Organic Personality Disorder-Explosive Type, and some patients with Organic Delusional Disorder. All of these patients responded to treatment with anti-cycling medications. METHODS

The patients were consecutive admissions to the Brain Injury and Behavior Program (BIBP) at the University of Pennsylvania between April, 1987, and November, 1989, with one of the following DSM-III-R diagnoses: 1) Organic Mood Disorder (OMD) -Manic or -Mixed; 2) Organic Personality DisorderExplosive Type (OPD-ET); or 3) Organic Delusional Disorder (episodic psychosis with prominent delusions, with absent or ambiguous mood symptoms; hallucinations and formal thought disorder, if present, were less prominent than delusional activity). Table 1 lists the neurological diagnosis, phenomenological subtype, and DSM-III-R category for the patients meeting these criteria. Nineteen patients were identified. Seventeen were initially evaluated as in-patients on the Neuropsychiatry Service of the Hospital of the University of Pennsylvania. The evaluation consisted of a complete physical, neurological and psychiatric examination; observation by the Unit Staff and the treatment team for a minimum of three weeks; radiological, electroencephalographic and neuropsychological testing, as indicated by the clinical condition; review of all obtainable previous records. Clinical diagnoses were determined by the primary psychiatrist (TWMcA or ASZ) in each case. Scores on the Mania Rating Scale (MRS) of Young et al. [21] were obtained on most patients admitted to the BIBP inpatient service as part of a standard battery of scales performed at the time of intake. Pre-treatment scores were obtained within the first week of hospitalization, or following withdrawal from previous psychotropic medications, if this was possible based upon the clinical condition. Post-treatment MRS scores were obtained by the same examiner at or near the time of discharge. Pre- and post-treatment scores were available on fourteen of the patients described here, including five with elated mania, four with irritable mania, and four with labilityhritability. Five of these patients were subsequently seen as out-patients for between seven and forty-three months at the time of this writing.

BIPOLAR AFFECTIVE DISORDERS / 381

Tivo patients were initially evaluated as out-patients. The evaluation consisted of a complete psychiatric examination by two psychiatrists, and review of the records of previous psychiatric and neurological evaluations and treatment, including electroencephalographic and neuroimaging studies. One of these patients was subsequently admitted to the in-patient unit for intensive monitoring and treatment; the other was treated exclusively on an out-patient basis. Both of these patients have been followed by one of the authors (ASZ) for thirty-two and thirty-six months, respectively, at the time of this writing. Treatment was instituted as indicated by the clinical presentation. The degree of clinical response was rated by the patient’s primary psychiatrist W c A or ASZ) on a scale of: complete remission, improved, mildly improved, or unimproved. For in-patients, the clinical response was rated at the time of discharge. The remaining patient was in a euthymic phase when evaluated as an out-patient; following institution of treatment, her mood cycling, previously occurring with a period of approximately four months, did not recur, and she was judged to be in complete remission. Cognitive status was monitored by bedside clinical evaluation, daily during the period of in-patient treatment, and during each office visit during subsequent out-patient follow-up. Serial neuropsychological test batteries were obtained on several of the patients who remained in long-term follow-up. Brief case histories, representative of each of the four clinical presentations, are presented. RESULTS AND SELECTED CASE REPORTS

Phenomenology Elated Mania

Of the nineteen patients meeting our inclusion criteria, seven had periods of elated mood, meeting DSM-111-R criteria for Acute Manic Episode. A representative case report follows. Case Number 2 (Elated man@) - A sixty-one-year-old female with a long history of tonic-clonic epilepsy, well controlled with phenytoin and phenobarbital for more than thirty years, was admitted to the hospital for treatment of an acute manic episode. She was described as being a well-educated, hard-working, artistic and talented woman all of her life, and had no history of psychiatric disease, family or interpersonal dysfunction, or substance abuse. Three weeks prior to admission, her daughter had arrived for a visit to find the patient elated and agitated, neglecting her usual activities. She was admitted to the psychiatric unit of a local hospital and treated with haloperidol, but soon discontinued the medication and left the hospital against medical advice. Her behavior became more bizarre, with frequent dance-like posturing, public disrobing, pressured speech,

382 / ZWIL. McALLlSTERAND RAIMO

Table 1. List of Patients, Showing Phenomenological Subtype, DSM-Ill-R Diagnostic Category, and Demographic Information Case

Neurological Diagnosis

Age

Sex

Phenom’l Subtype

DSM-Ill-R Diagnosis

1

Complex partial seizures S/P right anterior temporal lobectomy

37

F

Elated mania

OMD, manic

2

Generalized seizures Early dementia

61

F

Elated mania

OMD, manic

3

Generalized seizures Mixed connective tissue disease

63

F

Elated mania

OMD, manic

4

S/P frontal leukotomy

72

F

Elated mania

OMD, mixed

5

S/P closed head injury

25

M

Elated mania

OMD, mixed

6

S/P closed head injury

32

M

Elated mania

OMD, mixed (Rapid cycling)

7

Learning disability Generalized seizures

16

M

Elated mania

OMD, mixed (Rapid cycling)

8

Complex partial seizures S/P right anterior temporal lobectomy

32

M

Irritable mania

OMD, manic

9

Traumatic brain injury

24

M

Irritable mania

OMD, mixed

10

Anoxic encephalopathy

57

M

Irritable mania

OMD, mixed

11

Lupus cerebritis Anoxic encephalopathy Seizures

28

F

Irritable mania

OMD, mixed

12

Closed head injury Normal pressure hydrocephalus Seizures

30

M

Affective lability, irritability

OPD-ET OMD, depressed

BIPOLAR AFFECTIVE DISORDERS / 383

Table 1. (Cont’d.) Neurological Diagnosis

Age

Sex

13

Closed head injury

38

14

SIP resection of right parasellar meningioma

15

Phenom’l Subtype

DSM-Ill-R Diagnosis

M

Affective lability, irritability

OPD-ET Alcohol, sedative dependence

69

F

Affective lability, irritability

OPD-ET OMD, depressed

Closed head injury

31

M

Affective lability, irritability

OPD-ET OMD, depressed

16

Multiple CVA’s: bitemporal, right frontal, right occipital

67

M

Affective lability, irritability

OPD-ET Dementia

17

Progressive dementia

42

M

Affective lability, irritability

OPD-ET Dementia

18

SIP left parietal AVM excision Generalized seizures SIP closed head injury

40

M

Recurring psychosis

ODD

19

Parkinson’s disease

59

F

Recurring psychosis

ODD

Case

Note: OMD, organic mood disorder; OPD-ET, organic personality disorder-explosive type; ODD, organic delusional disorder.

delusions of persecution and grandiosity, agitated behavior, and elated affect. After admission to our hospital, she gradually improved on the combination of lithium citrate and haloperidol; haloperidol was discontinued prior to discharge, and the improvements were maintained on lithium monotherapy. Although she remained oriented throughout this episode, mild frontal release signs were noted, and neuropsychologicaltesting revealed diffuse cognitive deficits consistent with an early dementia.

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Irritable Mania

Four patients had periods of irritable, but not clearly elated, mood, associated with other signs and symptoms characteristic of mania; these patients met DSM-111-R criteria for Acute Manic Episode, and could be given a diagnosis of OMD-Manic or -Mixed, if the presence of irritable mania is allowed for that category. A representative case report follows: Case Number 8 (Irritable mania) -A thirty-year-old male was admitted to the BIBP in-patient service for treatment of an acute psychotic episode. He had a history of closed head injury, with loss of consciousness and a skull fracture, at three years of age, and complex partial seizures with secondary generalization, refractory to multiple anticonvulsant medications, since six years of age. Two months prior to admission he had undergone a right anterior temporal lobectomy, with subsequent improvement in seizure control. Two weeks prior to admission, his family noticed the onset of irritability, argumentativeness and impulsivity. His affect became labile, with rapid shifts between inappropriate laughter and tearful sadness. His appetite increased, and his sleep became disordered and fitful. He became hyperreligious, and joined a fundamentalist religious sect in which he had previously expressed no interest. He spent money excessively and foolishly. All of these symptoms were in marked contrast to his previous behavior and mental state. At the time of admission, his thoughts became progressively disorganized, and he became preoccupied with the belief that Martin Luther King was visiting his hospital room to give him advice. No periods of elation were reported by his family, or observed in the hospital. There was a history of one previous similar episode six years prior to admission, which had responded to a short course of haloperidol; there had been no recurrence of symptoms since that time, and no treatment with psychotropic medications. The present episode also cleared rapidly with haloperidol 12 mg daily, and the patient returned to his previous mental state. Following discharge, he was started on lithium carbonate and carbamazepine (the latter for prophylaxis of seizures as well as mania), and gradually weaned off of haloperidol. Another manic episode, similar to the one described above, occurred approximately two months following discontinuation of haloperidol, and resolved promptly with the addition of 5 mg of haloperidol daily. This patient has been monitored for three and one-half years following discharge, during which he has been euthymic, non-psychotic, and seizure-free on a regimen of lithium carbonate (1500 mg daily), carbamazepine (1200 mg daily) and haloperidol (5 mg daily); on two occasions, manic episodes recurred when the haloperidol was discontinued.

Affective Lability, Irritability

Six patients had mood lability and irritability, not meeting DSM-111-R criteria for Acute Manic Episode, and usually associated with explosive behavioral dyscontrol. By present standards, these patients would be classified as OPD-ET [20]. It is notable that three of these patients also received a diagnosis of

BIPOLAR AFFECTIVE DISORDERS / 385

OMD-Depressed, meeting DSM-III-R criteria for Acute Depressive Syndrome (i.e., Acute Depressive Episode criterion “A”) in addition to OPD-ET. A representative case report follows.

Case Number 13 (Lability, irritability, and episodic behavioral dyscontro1)A thirty-eight-year-old male was admitted to the BIBP in-patient service for detoxification and behavioral stabilization. He had a history of regular moderate alcohol use, but no history of psychiatric disease, prior to falling 20 or 30 feet from a roof to a concrete surface four years prior to admission. During the fall, he sustained a closed head injury with loss of consciousness for six hours, a right temporo-parietal contusion, and a right temporal intracerebral hematoma. Although he recovered without major neuromuscular residua, his mood became labile and his behavior became severely dyscontrolled. Violent outbursts of verbal and physical aggression, precipitated by trivial stressors and frustrations, occurred daily, during which he assaulted people and destroyed property. When enraged, he voiced lurid homicidal intentions against a variety of individuals, although he never acted upon these urges, and denied them when calm. He abused large amounts of alcohol and prescription sedatives, which further exacerbated his mood lability and aggressive behavior. He described his mood as pervasively depressed, even while calm; voiced frequent suicidal ideation during behavioral outbursts; and slept poorly. Following admission, he was weaned off of sedatives, and started on lithium carbonate and haloperidol. Over several weeks, his behavior improved dramatically, with a marked reduction in the incidence and severity of aggressive outbursts, and resolution of depression. Haloperidol was discontinued soon after discharge, without recurrence of the previous symptoms. He has remained stable, on lithium monotherapy, for thirty-two months of subsequent follow-up. Recurring Psychosis

Two patients had discrete periods of intense delusional ideation, and returned to a completely non-psychotic baseline between episodes. One of these patients also had auditory and visual hallucinations during the psychotic episodes, but these were much less prominent than the delusional symptoms. Neither of these patients had a prominent mood disturbance, either during or between the psychotic periods. These patients, which resembled those historically described as having “cycloid” or “episodic” psychoses, would receive a diagnosis of ODD by DSM-III-R criteria [l,121. A representative case report follows. Case Number 18 (Recurringpsychosis) -A forty-year-old male was admitted to the hospital for treatment of new-onset visual hallucinations three months following a closed head injury, with loss of consciousness for several hours, in a motor vehicle accident. He had a previous history of a stroke, followed by resection of a left temporo-parietal aneurysm, at sixteen years of age. Subsequently, he had suffered from generalized seizures which had intermittently

386 / ZWIL, McALLlSTER AND RAlMO

required anti-convulsant medications, but had no history of psychosis, depression, mania, aggressiveness or cognitive impairment. During the present hospitalization, he was found to have new-onset complex partial seizures. The visual hallucinations cleared completely with carbamazepine. Five months following discharge, he suffered the acute onset of a paranoid psychosis, marked by delusions that his psychiatrist was controlling his thoughts and actions via beams directed towards his head, that he was in hell and his psychiatrist was the Devil, and that he was becoming homosexual. He was re-admitted to the hospital where lithium carbonate was added to his regimen, and the psychotic symptoms resolved. Following discharge, however, lithium therapy was discontinued due to a fulminant exacerbation of acne, and psychotic symptoms recurred within five weeks. Subsequent attempts to control these symptoms with valproic acid, verapamil, nortriptyline and perphenazine were not successful. Lithium carbonate was re-started, with aggressive acne prophylaxis, and the psychotic symptoms again resolved. This disorder has subsequently remained in remission on the combination of lithium carbonate and carbamazepine, although brief episodes of breakthrough psychosis have occurred during periods of psychosocial stress, and have been managed by the addition of low-dose perphenazine during these periods. The patient has been completely euthymic between episodes, and no pathognomonic depression, elation, irritability or aggressive behavior have occurred during or between exacerbationsof psychosis. The content of the delusions has been largely consistent between episodes. Table 2 summarizes these findings.

Treatment Response All of the patients were treated with anti-cycling agents, either lithium, carbamazepine or both. Some were also treated with neuroleptics, anti-depressants, or beta-blockers, as indicated by their clinical conditions. Complete remission occurred in three patients, including the two with intermittent psychosis and one

Table 2. Summary of Phenomenological Groups Phenomenological Group Elated mania Irritable mania Lability, irritability Intermittent psychosis Total

Number of Patients 7 4

6 2 19

BIPOLAR AFFECTIVE DISORDERS / 387

patient with irritable mania. These three patients returned to a completely euthymic, non-psychotic state, identical to their mental status prior to onset of psychiatric symptoms, but subsequent to onset of their neurological disorders. Two of these patients had cognitive impairments secondary to their brain injuries; their cognitive status was not affected by the psychiatric episodes or their treatment. Eleven patients were classified as improved, with a significant reduction in symptoms and improvement in psychosocial status, although some symptoms and/or psychosocial impairment remained. Four patients were classified as mildly improved, although significant symptoms and psychosocial impairment, related directly to their affective disorders and not to cognitive or neurological symptoms, persisted. One patient, who had a progressive dementia and explosive behavioral dyscontrol, was judged to be unimproved despite treatment with lithium carbonate, a neuroleptic, and a sedative. Table 3 lists the medications used during the initial in-patient treatment (for the eighteen patients whose treatment was begun in the hospital) or during the initial course (for the patient who was treated solely on an out-patient basis). Cognitive status, as assessed daily by bedside cognitive examination, did not change appreciably during the treatment, in any patient. MRS scores declined in each of the fourteen cases. In one case (No. 17) the MRS score decreased, although the patient did not improve clinically. The mean decline was 18.7 points, and the scores of twelve patients declined by ten or more points. The pre-treatment scores of thirteen patients were above 27.3, the median score of patients meeting DSM-I11 criteria for Acute Manic Episode in a study investigating the correlation of MRS scores with severity of mania and response to treatment [39], and the post-treatment scores of twelve patients were below 20.3, the median post-treatment score in the same study. The scores of seven patients dropped to 14.0 or below, the score which has been reported to predict a favorable outcome following discharge from hospital [40]. Seven of the patients (Case numbers 6, 7, 8, 9, 13, 18, and 19) were subsequently treated as out-patients by one of the authors (ASZ), and five (Case numbers 6,8,13, 18, and 19) remain in treatment, or accessible to surveillance, at the time of this writing. Three of these patients (Case numbers 9, 13 and 19) maintained the initial improvement, without substantial changes in their medication regimens, throughout the follow-up period. Three patients (Case numbers 7, 8 and 18) subsequently required substantially higher doses, or additional medications, to maintain their improvements. One patient (Case number 6), who suffered from a rapid cycling bipolar disorder following a closed head injury, has maintained poor control after the initial improvement, with multiple manic and depressive exacerbations, despite multiple medication trials. Four of the patients (Case numbers 8,9,18 and 19) suffered recurrences of affective or psychotic symptoms when medications were decreased or discontinued, therapeutically or due to non-compliance, and regained their initial improvements when medications were re-started. In no case was it possible to eliminate any of the medications, without loss of the initial improvements. Bedside cognitive examination, performed

388 / ZWIL, McALLlSTER AND RAlMO

Table 3. Response to Treatment

Case

Treatment rota1 daily dosage (levers)]

Clinical Response

MRS Scores Pre

Post

Decrease

1

LiCO3 1200 mg (0.34) Haloperidol6 mg

Improved

27

6

21

2

Licitrate 900 mg (0.84) Haloperidol 8 mg Phenobarbital 100 mg (19.4) Phenytoin 100 mg Propranolol40 mg

Improved

40

5

35

3

LiCO3 900 mg (0.84) Carbamazepine 900 mg

Improved

28

3

25

4

Licitrate 300 mg Carbamazepine 200 mg

Mildly improved

32

18

14

Mildly improved

37

10

27

5 LiCO3 1800 mg (1.1) Perphenazine20 mg Propranolol80 mg 6

LiCO3 900 (0.75)

Improved

7

LiCO3 600 mg (0.4) Carbamzepine 600 mg (6.4) Nortriptyline 50 mg

Improved

8

LiCO3 1200 (0.70) Haloperidol 12 mg Benztropine 1 mg Phenytoin 200 mg Phenobarbital 120 mg

In remission

32

9

23

9

LiCO3 1200 mg (0.37) Pindolol 25 mg

Improved

31

23

8

10

LiCO3 450 mg (0.53) lsocarboxazid 20 mg

Improved

33

16

17

11

Carbamzepine 1200 mg lsocarboxazid 20 mg (Prednisolone60 mg)

Improved

32

32

8

BIPOLAR AFFECTIVE DISORDERS / 389

Table 3. (Cont'd.) Treatment rota1 daily dosage Case

eve?)]

Clinical Response

MRS Pre

Scores Post

Decrease

34

16

18

12

t i c 0 3 1500 (0.47) Carbamzepine 1600 mg

Mildly improved

13

LiC03 1200 mg (0.6) Haloperidol 6 mg Benztropine 1 mg

Improved

14

LiCO3 150 mg Carbamzepine 100 Methylphenydate 5 mg

Improved

31

14

17

15

LiCO3 1200 mg (1.1) Amitriptyline 75 mg

Improved

31

17

14

16

Carbamazepine 75 mg Lorazepam prn

Mildly improved

35

13

22

17

LEO3 1200 mg Mesoridizine 300 mg Lorazepam 2 mg

Unimproved

31

18

13

18

LiCO3 900 mg (0.50) Carbamzepine 1600 mg

In remission

19

LiCO3 600 mg (0.67)

In remission

'Serum level units: Lithium, m a ; Carbamazepinemg/L; Phenobarbital,mg/L.

during each office visit, detected no significant cognitive changes, in any of the patients, throughout the follow-up period. Serial neuropsychologicaltest batteries, obtained over the first two years following the head injury of Case number 6, revealed a gradual recovery of the initial cognitive deficits to pre-injury levels, despite an active and refractory mood disorder.

DISCUSSION The results presented in this article support the hypothesis that bipolar mood disorders may display a range of phenomenological characteristicsin patients with

390 / NVIL, McALLlSTER AND RAlMO

underlying neurological disease. This is supported by the cyclic or episodic nature of the symptoms observed in our patients, and by the favorable response to pharmacological agents known to be effective against bipolar mood disturbances. Clinical Interpretations

All but one of the patients described in this report improved following treatment with anti-cycling medications. In those patients whose symptoms did not resolve completely, a cessation or dampening of the episodic pattern was observed. Most notably, the two patients with episodic psychosis, and without prominent manic symptoms, experienced complete remissions following treatment with lithium alone (Case 19) or lithium and carbamazepine (Case number 18), in the absence of neuroleptics. All of these patients had stable or slowly progressive encephalopathies, the progression of which could not, by itself, explain the cyclic or episodic nature of the psychiatric symptoms. Seven of the patients (Cases number 1,2,3,7,8,11 and 18) had histories of seizures. In all cases, however, the seizures were in remission, or were well controlled with medications, during the initial treatment period, and there was no history of temporal correlations between active seizures and exacerbations of psychiatric symptoms. One patient (Case number 18; see detailed case report) originally presented with new-onset complex partial seizures and visual hallucinations, both of which resolved with carbamazepine monotherapy; it is likely that these isolated visual hallucinations were ictal or peri-ictal phenomena. However, he subsequently experienced the first episode of a qualitativelydifferent paranoid psychosis, accompanied by prominent auditory hallucinations, which resolved completely following the addition of lithium carbonate to the regimen; this episode, which constituted the initial treatment phase reported in this article, was not accompanied by active seizures. One patient (Case number 7) experienced intermittent break-through seizures during the subsequent follow-up period, during which he was psychiatrically stable; no exacerbations of his affective or behavioral symptoms, and no recurrence of cyclicity, correlated with seizure episodes. Although not directly etiological, the seizures may have been related to the psychiatric syndromes by one or both of two possible mechanisms: 1) the behavioral and epileptic symptoms may have been epi-phenomena associated with the same underlying neurological lesions; 2) the psychiatric disturbances may have been associated with electrical dischargeswhich, due to the path of their spread, produced only behavioral symptoms without the motoric and cognitive phenomena characteristicof complex partial seizures. Tucker et al. [41] proposed that the latter mechanism may provide a link between “atypical psychosis,” similar to the episodic psychoses of Monroe [30],and neurological dysfunction in temporal and limbic structures. One patient (Case number 11) had been intermittently treated with several courses of high-dose corticosteroid medication, which is known to precipitate

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mania and depression in certain individuals [6, 421, as treatment for systemic lupus erythematosus. A review of the history suggested that her bipolar mood disturbance was not due solely to these medications, but that the symptoms were probably exacerbated by them. At the time of her participation in this study, the medical consultant advised against discontinuingsteroid medications, and she was maintained on a stable dose of 60 mg of prednisolone daily throughout the observation and treatment period. Her symptoms, which at that time consisted of an irritable and dysphoric hypomania, improved significantly, but did not resolve completely, following treatment with carbamazepine and a monoamine oxidase inhibitor. This experience suggests that patients with medication-induced bipolar disorders, who are unable to be withdrawn from the offending agent, may still benefit from treatment with psychotropic medications. Lithium carbonate was the medication most often used in our series, due to its established position as the drug of choice for the treatment of idiopathic bipolar disorders [43], and to its reported efficacy in patients with episodic dyscontrol [5,24]. Four of the patients (Case numbers 3,7,11 and 18) experienced onset of their major psychiatric disturbances while receiving carbamazepine for seizure control, suggesting that lithium carbonate may be the more effective alternative in brain injured patients, as well. Several authors have suggested that patients with neurological disease may be more sensitive to the toxic effects of lithium and carbamazepine [44,45]. This was not observed in our patients, although an effort was made to use the lowest effective doses, and levels were kept in the low therapeutic ranges for most of these patients. The limited experience with longterm follow-up suggests that these medications must frequently be continued for long periods to prevent recurrence of symptoms.

Phenomenologyand Nosology The nosological significance of the phenomenological type of the mood disturbance (i.e., euphoria vs. irritability), occurring during episodes of mania secondary to brain disease, has not been clearly defined. In their original review, Krauthammer and Klerman [6] allowed the diagnosis of secondary mania to be made in the presence of either elated or irritable mood, in accordance with contemporary criteria for idiopathic mania, including those of the Diagnostic and Statistical Manual of Mental Disorders, Second Edition @SM-II) 1461. DSM-I11 [47] included Organic Affective Syndrome as a diagnostic category. Although the criteria themselves did not specify the nature of the mood changes, the descriptive text stated that “The clinical phenomenology of this syndrome is the same as that of a manic or major depressive episode” [47, p. 1171; the criteria for a manic episode allowed “One or more distinct periods with a predominantly elated, expansive or irritable mood” [47, p. 2081. DSM-111-R [3], however, did not include irritable mood in the criteria for Organic Mood Syndrome, Manic or Mixed Type, specifying only “elated, or expansive mood,” although “irritability

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or lability of mood” are mentioned in the descriptive text as possible “associated features” [3, p. 1121. Thus, patients with known neurological lesions and psychiatric disturbances characterized by irritable, but not elated or expansive, mood, and who may have been diagnosed as having a secondary bipolar disorder by earlier criteria, would be excluded by DSM-111-R criteria; the only DSM-111-R category available for such patients is OPD-ET. This diagnostic category can include patients with a known or presumed organic lesion who are subject to affective instability, irritability, intrusiveness, belligerence, and socially inappropriate or indiscreet behavior. This syndrome, which bears a descriptive resemblance to irritable mania, frequently results from frontal lobe injuries [20]. In our series of patients with affective changes associated with organic brain disease, irritable mood was more common than purely elated mood. This series suggests that there is a significant overlap between the manifestations of secondary mania and explosive organic personality disorder. This is in accord with the experience of ShuMa et al. [19], who reported that irritability and assaultiveness were common features of their patients with secondary mania. Furthermore, it suggests that these patients represent a spectrum of phenomenology, ranging through elated mania, irritable mania, episodic psychosis, and episodic behavioral dyscontrol. This supports the concept, proposed by Klerman [6,48], Akiskal[49] and others, that mania is a heterogeneous syndrome which can result from a variety of etiologies. Since the majority of our patients had diffuse or multifocal lesions, it was not possible to correlate phenomenological subtypes with the sites of injury, in this study. From a theoretical perspective, it may be that the level of behavioral activation may be a more reliable core symptom of mania than any specific mood disturbance [9,50,51]. The valance of any associated mood disturbance, and the degree of impulsivity, may be determined by the location or extent of the central nervous system injury. For example, a frontal lobe injury may lead to significant disinhibition; irritability and dysphoria may be associated with a left frontal injury; and euphoria and grandiosity may be associated with a predominantly right frontal or fronto-temporal injury. From a clinical perspective, the evaluation and treatment of neurologically impaired patients with mixed behavioral disturbances and prominent behavioral activation should include careful consideration of a bipolar spectrum diagnosis, and a trial of anti-cycling medication. This should include patients without prominent mood symptoms, who have previously been diagnosed as having explosive organic personality disorder or atypical psychosis. REFERENCES 1. M. Beckson and J. L. Cummings, NeuropsychiatricAspects of Stroke, International Journal ofpsychiatry in Medicine, 2l:l-15,1991.

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