Psychiatry for Neurologists - part 5 pptx

APATHY Epidemiology Previous studies show that apathy, defined as a state of diminished motivation, occurs in PD as an independent syndrome in about 12% of patients and co-exists with depressive disorders in at least 25% of patients. There are no clear predictors of apathy. The data are contradictory as to whether patients with independent apathetic syndromes have greater cognitive impairment. Certainly, apathy is a common component of dementia, delirium, or demoralization. Signs and Symptoms Apathy is manifest as a lack of motivation or initiative along with indifference about the degree of inactivity (8). There is usually diminished perseverance, interest in new things, and concerns over one’s health. Such patients generally enjoy themselves at arranged or structured activities, but they return to their usual inert state once the event is over. Patients fail to take an active interest in others and may be less conversational. They do not exhibit negativism, active social withdrawal, or anhedonia as seen with depressive disorders. Apathy is usually not distressing to the patient, but their inactivity and lack of spontaneous effort are frustrating to family members and caregivers, who tend to initiate complaints and wonder if the patient has a depressive disorder. Etiopathological Factors Goal-directed activity is associated with intact dopaminergic and prefrontal cortical activity, but apathetic syndromes commonly involve basal ganglia pathology. Evidence for neuronal loss in the locus coeruleus implicates a role for noradrenergic dysfunction. A role for abnormalities in frontal- subcortical circuitry is thus suggested. Parallels between features of apathy and those of PD, especially bradyphrenia and bradykinesia, suggest shared pathophysiological processes among these cognitive, behavioral, and motor aspects of the disease. One study showed strong associations between apathy, executive dysfunction, impairments in instrumental activities of daily living, and higher levodopa doses. No clear demographic or historic features distinguish apathetic syndromes from PD in general or compared with PD with depression. Diagnosis DSM-IV Text Revision(TR) uses the term “personality change with apathy secondary to a general medical condition (PD)” when there is an apathetic syndrome. There are no established criteria for diagnosing apathetic syndromes. Persistent and pervasive apathetic phenomena are often overlooked or misdiagnosed as a primary depressive disorder. Recognition of the symptoms or syndrome is important in order to guide treatment (8). Differential Diagnosis Neurological signs and symptoms such as akinesia, hypomimia, hypophonia, cognitive dysfunction, and bradyphrenia can confound recognition of apathy. It is critical to exclude other explanations, such as a depressive disorder or delirium. SSRI antidepressants, which are most frequently prescribed for depression in PD, can also cause apathy, but this has not been demonstrated specifically in PD. Course and Prognosis There are no specific studies on the course of apathy in PD or its impact on the long-term course of the disease. Physical inactivity contributes to physical deconditioning, which can aggravate motor disability and compound caregiver burdens. Treatment There are no studies on the treatment of apathy. Caregivers should be educated about apathy, executive dysfunction, and their manifestations. Families need to learn how to respond appropriately to the 168 Marsh and Friedman patient’s lack of motivation and encourage health-promoting behaviors, including medication compli- ance, which the patient is unlikely to initiate. Treatment of co-morbid depression is an obvious first step pharmacologically. There are reports of improved function with dopaminergic or noradrenergic medications, such as amphetamines, levodopa, dopamine receptor agonists, selegeline, amantadine. Anecdotally, the cognitive-enhancing agents that are cholinesterase inhibitors or N-methyl- D-aspartate antagonists have been helpful. SELECTIVE COGNITIVE IMPAIRMENTS AND DEMENTIA Epidemiology and Phenomenology Nearly all patients with PD demonstrate some degree of cognitive impairment that ranges from mild selective deficits to dementia (9). Commonly, cognitive decline is not obvious clinically and scores on dementia screening tests, such as the Mini-Mental State Exam (MMSE), are often in the “normal range,” even for individuals with dementia. Early in the disease course, the impairments are more selective and generally affect the domains of executive and visuospatial functions, memory, and attention. Cross-sectionally, about 25–40% of patients have dementia (10). Signs and Symptoms Executive dysfunction, which is especially common, involves impairments in the ability to process new information and anticipate, plan, initiate, maintain, and change behaviors. Patients with executive dysfunction complain of disorganization and distractibility that prevents them from completing tasks. Other affected cognitive domains include information-processing speed (bradyphrenia), explicit recall (with relative sparing of recognition memory), spatial planning, verbal fluency, and attention. The impact of these types of such deficits depends on individual circumstances, but they may contribute to disability that affects employment or independent living. Patients with more global impairments fall into three general subgroups. The first consists of an intensification of the selective deficits, especially in memory and information-processing speed. A second group shows wider involvement of cortical functions, including aphasia, apraxia, and memory deficits, but the clinical presentation remains distinct from Alzheimer’s disease (AD). A third group has clinical features consistent with both PD and AD, and the language deficits are especially pro- nounced relative to the two other subgroups. Etiopathological Factors Postmortem and imaging studies suggest that dementia in PD is associated with neuronal loss of the cholinergic cells of the basal forebrain. In addition to the typical findings of PD (Lewy bodies and neuronal loss in the substantia nigra pars compacta), there are often Alzheimer-type neuropathological changes (senile plaques and neurofibrillary tangles) in the limbic system and/or the cortex. However, most cases of PD-dementia do not meet neuropathological criteria for definite AD. Cortical Lewy bodies are observed in PD patients with and without dementia. Some PD patients will meet neuropathological criteria for dementia with Lewy bodies at more advanced stages. The selective cognitive impairments may involve dysfunction of nonmotor neural circuits, including mesolimbic and mesocortical dopaminergic projections. Bradyphrenia may be associated with noradrenergic cell loss. Dementia is also associated with increasing age, family history of dementia, depression, and more severe motor dysfunction. Anticholinergic medications, medication interactions, disturbed sleep, and co-morbid medical illnesses are extrinsic factors that contribute to cognitive impairment. Diagnosis There are no operational criteria for the diagnosis of cognitive impairments or dementia in PD. Patients and families should be asked specifically about acquired changes in thinking abilities, memory, language, and executive functions and how these changes affect function at work and home. Parkinson’s Disease 169 Differential Diagnosis Because dementia is not inevitable in PD, it is important to exclude other conditions. As for all patients with dementia, there should be a metabolic work-up. Brain imaging, although justifiable, is rarely of value. Cognitive impairments can lead to reduced social interactions, and this may be inter- preted as a sign of depression. However, depressive disorders are also associated with increased cognitive impairment, and can either aggravate or cause a dementia syndrome. Anti-parkinsonian and other medications with psychoactive effects can also have deleterious cognitive effects. As frank dementia develops later in the course of PD, early-onset dementia (i.e., coinciding with onset of PD motor signs or within the first few years), suggests dementia with Lewy bodies. Course and Prognosis The course and prognosis of selective cognitive deficits and dementia in PD is unclear, in part because of the lack of operational definitions. At end stages of the disease, about 70% of the patients have a severe dementia syndrome. Dementia is associated with an increased likelihood of co-morbid depression and/or psychosis, which increases caregiver burden and not uncommonly leads to nursing home admission. Treatment There are no standard treatments of cognitive deficits in PD. Factors, such as anticholinergic medications, that contribute to cognitive impairment and dementia should be addressed. Education about cognitive deficits, their impact, and potential compensatory strategies is helpful to patients and their families. Formal neuropsychological testing can help clarify areas of relative strengths versus vulner- abilities and serial testing can assess individual change. Cholinesterase inhibitors were shown to improve cognition in three double-blind placebo-controlled studies (11–13). Effects of other potential cognitive-enhancing agents (e.g., memantine, and neuroprotective agents) await further assessment. PSYCHOSIS Epidemiology and Phenomenology The term psychosis refers to the specific phenomena of hallucinations (sensory perceptions without a stimulus), delusions (fixed false beliefs despite evidence to the contrary), and thought disorder (a disturbance in the form of speech). The development of psychosis in PD is invariably associated with dopaminergic therapy. When hallucinations, particularly visual hallucinations, occur in the absence of dopaminergic treatment, the diagnosis of dementia with Lewy bodies should be considered. Hallucinatory experiences are considered “benign” when the patient has insight into their non- real nature and is not disturbed by them, but the ability to discriminate can vary, especially in the setting of dementia. “Illusions,” sensory distortions of real objects, are not strictly hallucinations, but are grouped with that category. A lamp is seen as a person, a fire hydrant as a dog, or a shadow as a lurk- ing animal. Many PD patients seem to develop illusions before hallucinations, but the prognostic sig- nificance of this is uncertain. Often, patients have insight into the non-real nature of these experiences, but may not reveal them to clinicians or family unless asked specifically. Hallucinations involve any sensory modality and occur in nearly 50% of patients over the course of the disease. Cross-sectionally, about 25–40% of patients experience hallucinations (14). The hallucinations are predominantly visual, and usually take the form of nonthreatening people—sometimes strangers, sometimes family or friends—who look real. They are often outside the house, people fixing the road, children climbing trees, and so on. Some people experience “presence hallucinations,” defined as the compelling feeling that someone is in the room behind the patient, forcing him or her 170 Marsh and Friedman to turn. “Passage” hallucinations consist of brief sightings of someone or something passing in the peripheral visual field. The patient typically sees the same hallucination each time. They may occur in the light or the dark, and tend to occur when the patient is alone, relaxing, watching TV, or read- ing. They usually ignore the patient although they may interact among themselves. Patients with insight into the non-real nature of their hallucinatory experiences may find them amusing. Patients who lack insight can become distressed and may have associated paranoia. Some patients feel a responsibility for their “house guests” and attempt to feed or tend to their presumed needs. Less than half the patients with visual hallucinations suffer from other types of hallucinations. About 10% of patients have auditory hallucinations; olfactory, tactile, and visceral hallucinations are less common (15). These forms of hallucinations almost invariably occur in people who also have visual hallucinations. In general, they are indistinct phenomena that do not involve the visual hallucination. That is, the patient may hallucinate people who are silent, and, at other times hear party noises or muf- fled speech outside the room. Reported prevalence rates for delusions are 3–30%. Delusions are generally of a paranoid nature. A common delusion is of spousal infidelity. Other delusional themes include concerns about abandonment, or people living in the house, planning harm, stealing money, purposefully misplacing items, spying, and so on. In nondemented patients the sensorium is clear and scores on tests of cognitive function, including the MMSE are normal. Frequently complicating the psychosis are both anxiety and depression. Other Etiopathological Factors Cognitive impairment, especially dementia, is the major risk factor for the development of psychosis (14). Aside from dementia, systemic disorders, particularly infections, contribute to development of psychotic symptoms, usually in the context of a delirium. Medication toxicity is also common. Renal failure, even if partial, will increase the risk of amantadine toxicity because it is excreted via the kidneys. Each of the anti-PD medications can induce delirium or psychosis with a normal sensorium, so drug toxicity from excess dosing should always be considered, as a patient may accidentally overdose. Other psychoactive medications (e.g., benzodiazepines, non-PD anticholinergic medications, antihistamines, opiates, steroids) can result in psychosis. In the absence of other contributing factors, such as a delirium, it should be kept in mind that the development of psychotic symptoms is “state- dependent.” Thus, the psychotic symptoms are dependent on several factors, including degree of sleep deprivation and stress, and not on the brain drug level alone. Goetz et al. demonstrated this by hospi- talizing a cohort of patients who had visual hallucinosis on L-dopa in their homes. None developed any psychotic symptoms with intravenous infusions of L-dopa in the hospital. Diagnosis The diagnosis of psychosis rests on the presence of hallucinations or delusions, irrespective of whether the patient has insight. A key diagnostic issue is whether the patient has psychotic symptoms in the context of a normal sensorium or if there is evidence for an encephalopathy, with fluctuating levels of awareness, alertness, and attention. It is common for the psychotic symptoms to be context- dependent. Thus, hallucinations are rarely experienced in the office setting and reports of delusions are more common than the actual experience of them in the presence of the doctor. It is critical to obtain information about the presence of psychotic symptoms from an informant because patients may not have adequate insight to report their abnormal beliefs or experiences, or simply forget about them when they are not present. Differential Diagnosis The differential diagnosis of PD-related psychosis includes encephalopathy (delirium), during which a global change in mentation with fluctuating levels of alertness and attention is frequently accompanied by confusion, disorientation, and psychotic symptoms. In patients with a dementia, there Parkinson’s Disease 171 will be greater confusion over their baseline level. The distinction between drug-induced visual hallucinations from Bonnet’s syndrome, in which elderly people, particularly those with visual impairment, develop benign complex visual hallucinations, may be impossible. If the hallucinations are drug-induced they should resolve with reductions in the medications. Parasomnias can also be difficult to distinguish from psychosis. Patients may act out a dream, as in rapid eye movement (REM) sleep behavior disorder, or awaken from a dream to experience its continuation while awake, or suffer a “REM intrusion” while awake but in a near sleep state. “REM intrusions” are brief dreams in twilight state. Vivid dreams will be reported the next morning as if the events had truly occurred. This can mimic hallucinatory experiences or delusional thinking. Course and Prognosis The enhanced use of safe and effective drugs to treat psychosis in PD has improved outcomes but the presence of psychosis carries a poor prognosis (16). Despite demonstrated improvements in psychotic symptoms in each of the two randomized controlled trials with low-dose clozapine, there was a 10% mortality rate during the 3-month trial, with deaths split evenly between the placebo- and drug- treated subjects. In a follow-up of the cohort from one clozapine trial, mortality was 25% at 22 months and nursing home placement occurred in 42%. There were, in addition, multiple hospitalizations, often for nonpsychiatric problems. Despite the use of clozapine in the first follow-up report, 69% of treated patients remained psychotic, albeit to a milder extent. Nondemented psychotic patients often developed dementia during the 22-month follow-up. This contrasted with a follow-up study on such patients before clozapine was used and there was 100% mortality by 16 months. Treatment When patients have insight, the first approach to treatment is to exclude a contributing medical condition such as pneumonia or urosepsis. Once this is done, medications must be reduced or economized as far as possible. Sometimes, non-PD medications such as anticholinergics, used for bladder hyper- activity, or anxiolytics can be discontinued. PD medications should be reduced or stopped depending on the effect on motor function. Although it has not been studied, we recommend tapering and dis- continuing one drug at a time rather than tapering all the drugs simultaneously. Cholinesterase inhibitors have been shown in open-label studies to reduce psychosis in PD and improve cognition, which may reduce the risk for psychosis. Thus, their use can be considered although definitive studies have not been conducted. Addition of an atypical antipsychotic should be considered when the psychotic symptoms are bothersome or if there is associated agitation, oppositional, or aggressive behavior that affects caregiving (17). Strong data supports the use of clozapine. Doses as low as 6.25 mg at bedtime are often effective, but the mean dose required in most studies is 25 mg per day. A large number of PD patients have been successfully treated with quetiapine. Because quetiapine does not require any blood monitoring and clozapine does, quetiapine has become the initial antipsychotic of choice for most American PD experts. Several randomized controlled trials have demonstrated that olanza- pine worsens motor function in PD patients so it should be avoided. The limited published data on risperidone also indicates that it worsens motor function. As of this writing, a single report, an open- label retrospective study suggests that aripiprazole is neither helpful nor well tolerated, however, further study will be needed to draw conclusions. BRAIN SURGERY FOR PD After a lengthy hiatus in which surgery for PD was extremely rare, limited primarily to thalamo- tomies for the treatment of refractory tremor, functional neurosurgery was resurrected to treat several motor problems in PD (18). It became apparent that ablative lesioning could be improved on by electrical stimulation to reduce the actual damage to the brain while simultaneously allowing a variety of stimulation parameters to be altered to better cope with individual variation and plasticity over time. 172 Marsh and Friedman Signs and Symptoms Deep brain stimulation (DBS) in PD has been associated with a variety of psychiatric outcomes (19). Most of these are direct physiological effects, whereas others occur because of profound changes in function that often alter family psychodynamics. The direct physiological consequences of DBS on mood have been reported, with some cases in detail (20,21). Observed effects include acute depression, delayed-onset depression, immediate relief of depression, apathy, euphoria, disinhibition, hallucinations, and a 10% incidence of acute mania in some series (22). A sub-clinical effect described in one report is a decline in the ability of patient who had received bilateral subthalamic nucleus (STN) DBS to assess facial emotions in other people. This type of effect could have a significant but hard to detect impact on patients’ quality of life (23). We note this only to illustrate that there may be subtle changes associated with DBS. Pallidotomy can cause affective and cognitive changes, but these appear to be less marked or common. Neurobiology The mechanisms for the various responses to STN DBS are unknown. The medial STN is believed to be connected to the limbic portion of the globus pallidus, the striatum, the prefrontal and cingulate cortices. There is a rich connection between portions of the frontal lobes and the STN. Other Etiopathological Factors Most of the factors inducing behavioral changes in the DBS patients remain unknown. Elec- trode location is a critical factor; too low a placement has induced depression, and relatively small changes in stimulator settings have been associated with dramatic alterations of mood. The presence of significant cognitive impairment puts the patient at risk for further cognitive declines after surgery. Diagnosis Identification of postoperative behavioral changes is not difficult, although it may be difficult to distinguish a primary effect of the stimulation from a secondary effect. A patient who has a poor response to surgery may develop a pervasive depressive disturbance, which presumably is different from a depressive disturbance induced physiologically by the stimulator settings. Differential Diagnosis Some behavioral effects may mimic drug-related effects, particularly psychosis. In general, anti- PD medications can be reduced with STN surgery, hence behavioral changes that are possibly medication-related may be handled by drug reduction. Course and Prognosis Whether the course of the behavioral abnormalities associated with DBS is the same or different than those that evolve naturally is unknown. The discrete stimulation-induced syndromes are recognized by either their appearance or resolution following DBS adjustment, and their resolution within seconds, which is atypical for sustained depressive or manic syndromes. Treatment DBS adjustments need to be made when a behavioral change is thought to be associated with the DBS itself. FATIGUE Fatigue is a symptom complex that has multiple meanings. Whereas PD patients suffer from objectively measurable muscle fatigue with repeated muscle contractions, the fatigue discussed here is a “sense of tiredness, lack of energy or total body give out” (25). It is a subjective perception that is one Parkinson’s Disease 173 of the most common symptoms in all of medicine. There are few disorders, physical or mental, not associated with an increase in fatigue. Epidemiology Hoehn and Yahr noted in 1967 that fatigue alone was a rare presenting feature of PD. In surveys of PD patients, however, fatigue was common, affecting half, and was typically long lasting. In addition, half the patients who suffer from fatigue consider it to be as bad as their other symptoms. Neurobiology The underlying physiology of fatigue is unknown. Evoked potentials have demonstrated differences in responses in fatigued versus nonfatigued PD populations but how these relate to the perception of fatigue is unknown. Objectively demonstrable muscle fatigue, and physiological measures of exercise efficiency such as oxygen utilization for exercise tasks do not correlate with perceptions of fatigue (26). The overlap between mood and fatigue is so large that it is likely multiple factors are involved in the development of fatigue, which often predates the diagnosis of PD. Etiopathological Factors The “causes” of fatigue are unknown. There is an association between fatigue and depressed mood, but nondepressed patients often suffer from fatigue (27). Fatigue may be associated with sleep disturbances but successful treatment of excessive daytime sleepiness may not improve true fatigue. Fatigue does not correlate with motor dysfunction, duration of disease, or age. It does correlate with the self-perception of poor health. Diagnosis The diagnosis of fatigue rests on the patient’s report, or response to questioning (28). It cannot be demonstrated on examination as it does not correlate with muscular fatigue. Differential Diagnosis The overlap between fatigue and depression is large enough that fatigued patients should be evaluated for depression. They may have both. Other explanations for the fatigue should be considered, particularly other medical illnesses such as heart failure, anemia, hypothyroidism, and the like. Low blood pressure is another consideration, although not documented in published series. The overlap between sleepiness and fatigue is another area where interventions may be helpful. Patients should be evaluated for excessive daytime sleepiness, which may be perceived as fatigue and which may be treatable. Course and Prognosis Only one study has been published looking at long-term outcome. Those results were discourag- ing. Patients who were fatigued when the first prevalence survey was taken remained fatigued when assessed 9 years later, despite treatment attempts. On the other hand, patients who were not suffering with depression initially were very unlikely to develop it. Overall, the fatigue worsened over time. Treatment There is no treatment known for fatigue in PD. Whereas amantadine improves fatigue in multiple sclerosis , there is no data to suggest it helps in PD (28). Dopamine agonists have been implicated in worsened fatigue but this may be a confound resulting from their sedating side effect. Modafanil has been shown to improve excessive daytime sleepiness but not fatigue. Antidepressants have not been adequately studied but appear to improve mood without resolving the fatigue. Endurance training has been shown to improve fatigue in patient with other medical conditions including chemotherapy and cancer. It has not been tested in PD. Patients often reject this intervention, describing themselves as desirous but too fatigued to begin an exercise program. A role for stimulants such as amphetamines has been advocated but no data supports their use. 174 Marsh and Friedman IMPULSE CONTROL AND COMPULSIVE BEHAVIORS Although rare, there are behavioral abnormalities that appear to be drug-related that have attracted much attention and can be especially problematic (29). The first is hypersexuality. When L-dopa was first introduced, it was considered by some to be an aphrodisiac. In recent times, the anti-PD medications have been recognized as causing hypersexuality as well as abnormal sexual behaviors such as cross-dressing, exhibitionism, and even zoophilia (30). These activities are rare but can be very dis- ruptive or distressing. The treatment approach is uncertain. Reducing dopaminergic medications, especially dopamine agonists, behavioral counseling, and antipsychotic and medications are the usual treatment routes. Medications that help with impulsivity, such as SSRIs, or mood stabilizers are also tried. The patient’s day should be structured so opportunities for the behavior are limited, especially if it carries a risk of harm to others or the patient. Psychiatric hospitalization may be necessary to gain behavioral control. Pathological gambling resulting from anti-PD medications is relatively rare, but devastating (29, 31). Patients and families should be specifically warned about the potential for pathological gambling as most patients are not aware that this behavioral change is related to medication changes. Even those who have never gambled may attribute their behavior to changes in circumstances and, until it becomes problematic, finding a new source of enjoyment. As with hypersexual behavior, the treatment is uncertain, but the same medication approaches are used. In addition, families or others often need to take complete control of the finances and limit the patient’s access to money and gambling opportunities. “Punding,” a syndrome first described in amphetamine addicts, refers to an obsessive-compulsive- like fascination (29) with handling objects and taking them apart, usually with less success at putting them together again. Patients may catalog their jewelry or enter sums on a calculator, as in balancing a checkbook, endlessly. Although patients may recognize their behaviors as abnormal, they do not find them disquieting and thus do not ask for help. These behaviors, however, may lead to inattention to other more vital matters, which can cause others to raise concerns. Less problematic are other perseverant behaviors that also are drug-related, such as producing soft “sucking” sounds, humming single tunes, or making stereotyped gestures. In some cases, these behaviors are compulsive (i.e., repetitive acts that the patient feels driven to perform and leads to a relief in anxiety). Unlike the punding and gambling, these syndromes may bother patients so that they complain about them. Treatment involves lowering or altering the anti-PD medications or possibly adding an SSRI. ACKNOWLEDGMENTS Support for manuscript preparation by Dr. Marsh provided by the Johns Hopkins Medical Institutions Morris K. Udall Parkinson’s Disease Research Center of Excellence (NIH, P50-NS-58377). REFERENCES 1. Aarsland D, Larsen JP, Lim NG et al. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999; 67:492–496. 2. Menza M, Marsh L. Psychiatric issues in Parkinson’s disease: a practical guide. London: Taylor and Francis. In press. 3. McDonald WM, Richard I, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry 2003;54:1363–1375. 4. Leentjens AFG, Marinus J, Van Hilten JJ, Lousberg R, Verhey FRJ. The contribution of somatic symptoms to the diagnosis of depressive disorder in Parkinson’s disease: a discriminant analytic approach. J Neuropsychiatry Clin Neurosci 2003:15:74–77. 5. Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Rel Disord 2002;8:193–197. 6. Marsh L. Anxiety disorders in Parkinson’s Disease. Intl Rev Psychiatry 2000;12:307–318. 7. Richard IH, Justus AW, Kurlan R. Relationship between mood and motor fluctuations in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001;13:35–41. 8. Pluck GC, Brown RG. Apathy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002;73:636–642. 9. Dubois B, Pillon B. Cognitive deficits in Parkinson’s disease. J Neurol 1997; 244:2–8. Parkinson’s Disease 175 10. Dubois B, Pillon B. Dementia in Parkinson’s disease. In: Wolters EC, Sheltens Ph, Berendse HW, eds. 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We focus primarily on depression and neuropsychological impairment, as most of the empirical literature examined these two areas. However, we briefly describe other areas including pathological laughing and crying (PLC), anxiety, anger, and bipolar disorder. EPIDEMIOLOGY AND ETIOLOGY Depression It is widely agreed that depression is one of the more common symptoms in MS (1–3). Twelve- month prevalence of major depressive disorder (MDD) is 15–26%, with younger patients being more likely to be depressed (4). However, nearly half of all MS patients experience significant levels of depressive symptoms at any given point in time (5), and the lifetime prevalence of MDD following an MS diagnosis is approx 50% (6). These rates of depression are higher in MS than in other chronic illnesses (7,8) and other neurological disorders (9,10). Whereas the natural history of depression in MS has not been adequately studied, examination of control conditions in intervention studies suggest that depression in MS, left untreated, is not self-limiting (11). Depression in MS likely has multiple etiologies. It clearly has psychosocial origins. Loss of function in MS is unpredictable, and for many patients, unrelenting. Although absolute level of cognitive and physical impairment is not necessarily related to adjustment or depression (9,12–14), patient’s perceptions of the uncertainty (15), variability in disease (16), and the perceived intrusiveness of disease on daily activities (17–19) are all related to depression and adjustment. Loss of social support and social role functioning, which are associated with the disease, have also been shown to be associated with depression (20–23). Although the psychological sequelae of MS are associated with depression, this alone does not account for the higher rates of depression in MS compared to rates found in patients with other pro- gressive diseases. We have, therefore, proposed an etiological model that includes increased risk from both MS pathological and MS pathogenic factors. MS brain lesion volume, particularly in the frontal and temporal regions, have consistently been associated with increased risk of MDD and greater severity of depressive symptoms (24–26). It is increasingly accepted that some proinflammatory cytokines can induce and/or aggravate symptoms of depression in the general population (27). Consistent with this literature, there is evidence in MS that depression is strongly associated with disease exacerbation, From: Current Clinical Neurology: Psychiatry for Neurologists Edited by: D.V. Jeste and J.H. Friedman © Humana Press Inc., Totowa, NJ [...]... 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Neurology 2003;61: 152 4– 152 7. 5. Chwastiak. symptoms. Intramuscular IFN-β 1-a and IFN-β 1-b have been shown to help preserve cognitive functioning, whereas no effect on cognition has been seen for glatiramer acetate (1 05 107). IFN-β 1-b has been shown. Brain 1986;109 :58 5 59 7. 10. Whitlock FA, Siskind MM. Depression as a major symptom of multiple sclerosis. J Neurol Neurosurg Psychiatry 1980;43:861–8 65. Multiple Sclerosis 1 85 Table 2 Recommendations for