Psychiatry for Neurologists - part 5 pptx

There are reports of improved function with dopaminergic or noradrenergicmedications, such as amphetamines, levodopa, dopamine receptor agonists, selegeline, amantadine.Anecdotally, the

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 seenwith 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 complaintsand wonder if the patient has a depressive disorder

Etiopathological Factors

Goal-directed activity is associated with intact dopaminergic and prefrontal cortical activity, butapathetic syndromes commonly involve basal ganglia pathology Evidence for neuronal loss in thelocus 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, espe-cially bradyphrenia and bradykinesia, suggest shared pathophysiological processes among thesecognitive, behavioral, and motor aspects of the disease One study showed strong associations betweenapathy, executive dysfunction, impairments in instrumental activities of daily living, and higher levo-dopa doses No clear demographic or historic features distinguish apathetic syndromes from PD ingeneral or compared with PD with depression

Diagnosis

DSM-IV Text Revision(TR) uses the term “personality change with apathy secondary to a generalmedical condition (PD)” when there is an apathetic syndrome There are no established criteria fordiagnosing 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 tion, 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 prescribedfor depression in PD, can also cause apathy, but this has not been demonstrated specifically in PD

dysfunc-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 motordisability and compound caregiver burdens

Treatment

There are no studies on the treatment of apathy Caregivers should be educated about apathy, utive dysfunction, and their manifestations Families need to learn how to respond appropriately to the

exec-patient’s lack of motivation and encourage health-promoting behaviors, including medication ance, which the patient is unlikely to initiate Treatment of co-morbid depression is an obvious firststep pharmacologically There are reports of improved function with dopaminergic or noradrenergicmedications, such as amphetamines, levodopa, dopamine receptor agonists, selegeline, amantadine.Anecdotally, the cognitive-enhancing agents that are cholinesterase inhibitors or N-methyl-D-aspartateantagonists have been helpful.

compli-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 “normalrange,” even for individuals with dementia Early in the disease course, the impairments are more selec-tive 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 processnew information and anticipate, plan, initiate, maintain, and change behaviors Patients with execu-tive dysfunction complain of disorganization and distractibility that prevents them from completingtasks Other affected cognitive domains include information-processing speed (bradyphrenia), explicitrecall (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 con-tribute to disability that affects employment or independent living

Patients with more global impairments fall into three general subgroups The first consists of anintensification of the selective deficits, especially in memory and information-processing speed Asecond group shows wider involvement of cortical functions, including aphasia, apraxia, and memorydeficits, but the clinical presentation remains distinct from Alzheimer’s disease (AD) A third grouphas 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 ofthe 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

neuropatholog-ical 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 CorticalLewy bodies are observed in PD patients with and without dementia Some PD patients will meetneuropathological criteria for dementia with Lewy bodies at more advanced stages The selective cog-nitive impairments may involve dysfunction of nonmotor neural circuits, including mesolimbic andmesocortical dopaminergic projections Bradyphrenia may be associated with noradrenergic cell loss.Dementia is also associated with increasing age, family history of dementia, depression, and moresevere motor dysfunction Anticholinergic medications, medication interactions, disturbed sleep, andco-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

Differential Diagnosis

Because dementia is not inevitable in PD, it is important to exclude other conditions As for allpatients with dementia, there should be a metabolic work-up Brain imaging, although justifiable, israrely 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 cog-nitive impairment, and can either aggravate or cause a dementia syndrome Anti-parkinsonian and othermedications with psychoactive effects can also have deleterious cognitive effects As frank dementiadevelops 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 partbecause of the lack of operational definitions At end stages of the disease, about 70% of the patientshave a severe dementia syndrome Dementia is associated with an increased likelihood of co-morbiddepression and/or psychosis, which increases caregiver burden and not uncommonly leads to nursinghome admission

Treatment

There are no standard treatments of cognitive deficits in PD Factors, such as anticholinergic cations, that contribute to cognitive impairment and dementia should be addressed Education aboutcognitive deficits, their impact, and potential compensatory strategies is helpful to patients and theirfamilies 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

medi-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

with-out 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 associatedwith dopaminergic therapy When hallucinations, particularly visual hallucinations, occur in theabsence of dopaminergic treatment, the diagnosis of dementia with Lewy bodies should be consid-ered 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 aregrouped 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

hal-lucinations are predominantly visual, and usually take the form of nonthreatening people—sometimesstrangers, sometimes family or friends—who look real They are often outside the house, people fixingthe 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

to turn “Passage” hallucinations consist of brief sightings of someone or something passing in theperipheral 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 ing They usually ignore the patient although they may interact among themselves Patients with insightinto the non-real nature of their hallucinatory experiences may find them amusing Patients who lackinsight can become distressed and may have associated paranoia Some patients feel a responsibilityfor their “house guests” and attempt to feed or tend to their presumed needs

read-Less than half the patients with visual hallucinations suffer from other types of hallucinations About10% 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 Acommon 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, includ-ing 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

psy-chosis ( 14 ) Aside from dementia, systemic disorders, particularly infections, contribute to

develop-ment 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 viathe kidneys Each of the anti-PD medications can induce delirium or psychosis with a normal senso-rium, so drug toxicity from excess dosing should always be considered, as a patient may accidentallyoverdose 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 sleepdeprivation 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 developedany psychotic symptoms with intravenous infusions of L-dopa in the hospital

Differential Diagnosis

The differential diagnosis of PD-related psychosis includes encephalopathy (delirium), duringwhich a global change in mentation with fluctuating levels of alertness and attention is frequentlyaccompanied by confusion, disorientation, and psychotic symptoms In patients with a dementia, there

will be greater confusion over their baseline level The distinction between drug-induced visual lucinations from Bonnet’s syndrome, in which elderly people, particularly those with visual impair-ment, develop benign complex visual hallucinations, may be impossible If the hallucinations aredrug-induced they should resolve with reductions in the medications Parasomnias can also be diffi-cult 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

hal-a “REM intrusion” while hal-awhal-ake but in hal-a nehal-ar sleep sthal-ate “REM intrusions” hal-are brief drehal-ams intwilight state Vivid dreams will be reported the next morning as if the events had truly occurred Thiscan 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

psy-chotic 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 treated subjects In a follow-up of the cohort from one clozapine trial, mortality was 25% at 22 monthsand nursing home placement occurred in 42% There were, in addition, multiple hospitalizations, oftenfor nonpsychiatric problems Despite the use of clozapine in the first follow-up report, 69% of treatedpatients remained psychotic, albeit to a milder extent Nondemented psychotic patients often devel-oped dementia during the 22-month follow-up This contrasted with a follow-up study on such patientsbefore clozapine was used and there was 100% mortality by 16 months

dis-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 requireany blood monitoring and clozapine does, quetiapine has become the initial antipsychotic of choicefor 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 onrisperidone 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, fur-ther 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 tomies for the treatment of refractory tremor, functional neurosurgery was resurrected to treat several

thalamo-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 ety of stimulation parameters to be altered to better cope with individual variation and plasticity overtime

vari-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 infunction 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

depres-sion, delayed-onset depresdepres-sion, immediate relief of depresdepres-sion, apathy, euphoria, disinhibition,

hallu-cinations, 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 cingulatecortices 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 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 Thepresence of significant cognitive impairment puts the patient at risk for further cognitive declinesafter surgery

Elec-Diagnosis

Identification of postoperative behavioral changes is not difficult, although it may be difficult todistinguish a primary effect of the stimulation from a secondary effect A patient who has a poorresponse to surgery may develop a pervasive depressive disturbance, which presumably is differentfrom 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 ication-related may be handled by drug reduction

med-Course and Prognosis

Whether the course of the behavioral abnormalities associated with DBS is the same or differentthan those that evolve naturally is unknown The discrete stimulation-induced syndromes are recog-nized by either their appearance or resolution following DBS adjustment, and their resolution withinseconds, which is atypical for sustained depressive or manic syndromes

of the most common symptoms in all of medicine There are few disorders, physical or mental, notassociated 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 tion, half the patients who suffer from fatigue consider it to be as bad as their other symptoms

addi-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 offatigue is unknown Objectively demonstrable muscle fatigue, and physiological measures of exer-cise 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 withthe 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 ated 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 Lowblood pressure is another consideration, although not documented in published series The overlapbetween sleepiness and fatigue is another area where interventions may be helpful Patients should

evalu-be evaluated for excessive daytime sleepiness, which may evalu-be perceived as fatigue and which may evalu-betreatable

Course and Prognosis

Only one study has been published looking at long-term outcome Those results were ing Patients who were fatigued when the first prevalence survey was taken remained fatigued whenassessed 9 years later, despite treatment attempts On the other hand, patients who were not sufferingwith depression initially were very unlikely to develop it Overall, the fatigue worsened over time

discourag-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 hasbeen shown to improve excessive daytime sleepiness but not fatigue Antidepressants have not beenadequately studied but appear to improve mood without resolving the fatigue Endurance training hasbeen shown to improve fatigue in patient with other medical conditions including chemotherapy andcancer It has not been tested in PD Patients often reject this intervention, describing themselves asdesirous but too fatigued to begin an exercise program A role for stimulants such as amphetamineshas been advocated but no data supports their use

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 wasfirst introduced, it was considered by some to be an aphrodisiac In recent times, the anti-PD med-ications 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 usualtreatment routes Medications that help with impulsivity, such as SSRIs, or mood stabilizers are alsotried 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 gainbehavioral 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 thosewho have never gambled may attribute their behavior to changes in circumstances and, until it becomesproblematic, finding a new source of enjoyment As with hypersexual behavior, the treatment is uncer-tain, but the same medication approaches are used In addition, families or others often need to takecomplete 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 findthem disquieting and thus do not ask for help These behaviors, however, may lead to inattention toother 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 iors are compulsive (i.e., repetitive acts that the patient feels driven to perform and leads to a relief inanxiety) Unlike the punding and gambling, these syndromes may bother patients so that they com-plain about them Treatment involves lowering or altering the anti-PD medications or possibly adding

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.

10 Dubois B, Pillon B Dementia in Parkinson’s disease In: Wolters EC, Sheltens Ph, Berendse HW, eds Mental tion in Parkinson’s disease II Utrecht: Academic Pharmaceutical Productions; 1999:165–176.

dysfunc-11 Aarsland D, Laake K, Larsen JP, Janvin C Donepezil for cognitive impairment in Parkinson’s disease: a randomized trolled study J Neurol Neurosurg Psychiatry 2002;72:708–712.

con-12 Leroi I, Brandt J, Reich SG, et al Randomized placebo-controlled trial of donepezil for cognitive impairment in Parkinson’s disease Intl J Ger Psychiatry 2004;19:1–8.

13 Emre M, Aarsland D, Albanese A, et al Rivastigmine for dementia associated with Parkinson’s disease N Engl J Med 2004;351(24):2509–2518.

14 Aarsland D, Larsen JP, Cummings JL, Laake K Prevalence and clinical correlates of psychotic symptoms in Parkinson Disease A community-based study Arch Neurol 1999;56:595–601.

15 Poewe W Psychosis in Parkinson’s disease Mov Disord 2003;18:S80–S87.

16 Factor SA, Feustel PJ, Friedman JH, et al Long term outcome of Parkinson’s disease patients with psychosis Neurology 2003;60:1756–1761.

17 Fernandez HH, Trieschmann ME, Friedman JH Treatment of psychosis in Parkinson’s disease: Safety considerations Drug Saf 2003;26:643–659.

18 Baron MS, Vitek JL, Bakay RA, et al Treatment of advanced Parkinson’s disease by unilateral posterior GPi tomy: 4-year results of a pilot study Mov Disord 2000; 5:230–237.

pallido-19 Anderson KE, Mullins J Behavioral changes associated with deep brain stimulation surgery for Parkinson’s disease Curr Neurol Neurosci Rep 2003;3:306–313.

20 Berney A, Vingerhoets F, Perrin A, et al Effect on mood of subthalamic deep brain stimulation for Parkinson’s disease:

a consecutive series of 24 patients Neurology 2002;59:1427–1429.

21 Funkiewiez A, Ardouin C, Caputo E, et al Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood and behavior in Parkinson’s disease J Neurol Neurosurg Psychiatry 2004;75:834–839.

22 Kulisevsky J, Berthier ML, Gironell A, Pascual-Sedano B, Molet J Parés P Mania following deep brain stimulation for Parkinson’s disease Neurology 2002;59:1421–1424.

23 Dujardin K, Blairy S, Debfevre L, et al Subthalamic nucleus stimulation induces deficits in decoding emotional facial expressions in Parkinson’s disease J Neurol Neurosurg and Psychiatry 2004;75:202–208.

24 Saint-Cyr JA, Trepanier LL, Kumar R, Lozano AM, Lang AE Neuropsychological consequences of chronic bilateral lation of the subthalamic nucleus in Parkinson’s disease Brain 2000;123:2091–2108.

stimu-25 Friedman JH, Chou KL Sleep and fatigue in Parkinson’s disease Parkinsonism Relat Disord 2004;10(Suppl 1):S27–S35.

26 Garber CE, Friedman JH Effects of fatigue on physical activity in patients with Parkinson’s disease Neurology 2003:60: 1119–1124.

27 Herlofson K, Larsen JP The influence of fatigue on health-related quality of life in patients with Parkinson’s disease Acta Neurol Scand 2003;107:1–6.

28 Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD The fatigue severity scale Application to patients with multiple sclerosis and systemic lupus erythematosis Arch Neurol 1989;46:1121–1123.

29 Kurlan R Disabling repetitive behaviors in Parkinson’s disease Mov Disord 2004;19:433–437.

30 Uitti R, Tanner CM, Rajput AH, Goetz CG, Klawans HL, Thiessen B Hypersexuality with antiparkinsonian therapy Clin Neuropharmacol 1989;12:375–383.

31 Voon V Repetition, repetition, and repetition: compulsive and punding behaviors in Parkinson’s disease Mov Disord 2004; 19:367–370.

15

Neuropsychiatric Disorders in Multiple Sclerosis

David C Mohr and Darcy Cox

INTRODUCTION

In this chapter, we review the empirical literature on the epidemiology, etiology, consequences, andtreatment of neuropsychiatric disturbance associated with multiple sclerosis (MS) We focus primar-ily on depression and neuropsychological impairment, as most of the empirical literature examinedthese 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

sug-gest 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 tion in MS is unpredictable, and for many patients, unrelenting Although absolute level of cognitive

func-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 dis- ease 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

asso-ciated with depression ( 20–23 ).

Although the psychological sequelae of MS are associated with depression, this alone does notaccount 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 fromboth MS pathological and MS pathogenic factors MS brain lesion volume, particularly in the frontaland temporal regions, have consistently been associated with increased risk of MDD and greater sever-

ity 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

measured both clinically and by gadolinium-enhancing magnetic resonance imaging (MRI) ( 28,29 ).

Thus, depression may be a product of specific MS-related autoimmune disease processes, as well asthe neurological damage caused by these processes This would indicate that depression could be both

a complication associated with MS, as well as a symptom of MS

In rare cases, depression may be an iatrogenic effect of medications The oral or intravenous

gluco-corticoids used to treat exacerbations can produce changes in mood and cognition ( 30 ) There has

also been some speculation that new-onset or increased depression may be an iatrogenic effect ciated with some of the disease modifying medications (DMMs) commonly used to treat MS.Specifically, early uncontrolled studies suggested that the interferon (IFN)-β may be associated with

asso-increased risk of depression ( 31–33 ) However, more recently studies have consistently and clearly

shown that IFN-β does not cause increases in depressive symptoms ( 34,35 ) Some patients may show

an increase in depressive symptoms following initiation of DMMs, however, this is likely an artifactresulting from a pre-initiation drop in depression associated with increased optimism immediately

prior to initiation ( 36 ) Thus, an observed increase in depression represents a return to baseline

depres-sion rather than an effect of the medication

Anxiety and Anger

Compared to depression, little has been written on anxiety in MS Given the degree of uncertainty

and the perceived potential threat of the disease ( 15,37,38 ) it is not surprising that the rates of ety are higher in MS than those found in the normal population ( 39 ) The point prevalence of prob- lems with anxiety has been estimated at between 19 and 34% ( 40–42 ) One study has suggested that anxiety is more common than depression ( 43 ).

anxi-Anxiety can have several sequelae anxi-Anxiety can aggravate depression in MS and is associatedwith increased rates of suicidal ideation, compared to depressed MS patients with little or no anxi-

ety ( 43 ) Anxiety is also related to decreased adherence to DMMs, which are all administered by

injec-tion Anticipatory injection anxiety is related whether or not the patient is able to self-inject, and

self-injection is associated with adherence ( 44 ) Experienced injection anxiety is also directly related

to adherence

Clinicians have frequently noted anger in MS patients ( 45,46 ) However, there is little empirical

literature in this area Anger is an appropriate response to the frustrations of having a chronic illnessand encountering new physical limitations It becomes problematic when the intensity of the angercauses distress, and/or when the anger is displaced onto others in the environment This is an impor-tant area that deserves greater research efforts

Pathological Laughing and Crying (PLC) and Euphoria

PLC has been used synonymously with pseudobulbar affect PLC is defined as bouts of lable laughing, crying, or both in response to nonspecific stimuli in the absence of a matching mood

uncontrol-state ( 47 ) It is estimated that PLC occurs in approx 5–10% of MS patients ( 48 ) It is generally ated with greater physical and cognitive disability PLC is generally responsive to fluoxetine ( 49 ) and fluvoxamine ( 50 ) Euphoria is a similar condition in which the patient’s mood is consistently cheerful

associ-and he or she is seemingly unaware or unconcerned with his or her condition Estimates of the lence of euphoria vary from 5 to 48%, although in our experience the lower number is likely more accu-

preva-rate Euphoria is a symptom of MS because it is associated with greater lesion load in the brain ( 9,51 ).

Extreme caution should be used in ascribing symptoms such as PLC or euphoria to psychological causessuch as repression or denial, particularly in patients with substantial cognitive impairment

Cognitive Impairment

Cognitive impairment is very common in MS, with an estimated point prevalence of 40–75% and

a lifetime prevalence closer to 75% Whereas prevalence is higher in patients with advanced disease,significant cognitive impairment symptoms can also present at onset or early in the disease course,

and in patients with very low levels of physical disability ( 52,53 ).

due to Multiple Sclerosis” ( 54 ) Patients can also experience cognitive dysfunction as a result of severe

depression, severe fatigue, or medication side effects

Cognitive disorder NOS due to MS, the most common form of cognitive impairment, is a muchmilder condition than dementia due to MS Patients with cognitive disorder NOS due to MS may com-plain of a number of subtle cognitive problems, including difficulty with memory, attention, multi-tasking, word-finding, visuospatial learning, memory, and organization, and problems with

organization and scheduling ( 55–59 ) The presentation of cognitive problems across patients is

het-erogeneous It is also important to recognize that patients can have significant cognitive problems, butcan have memory function preserved

Dementia due to MS is characterized by severe memory impairment and severe impairment in atleast one other cognitive domain, which may manifest as aphasia, apraxia, agnosia, or disturbed exec-utive functioning This impairment must be of sufficient severity to produce a readily apparent func-tional decline in most areas of the patient’s life, regardless of the patient’s level of physical functioning.Fortunately, dementia due to MS is relatively uncommon It typically occurs either very late in thedisease course or in the course of unusually aggressive disease

A number of neuropathological findings have been associated with cognitive dysfunction in MSpatients Lesion volumes derived from conventional T2 and T1 MRI have generally shown moderate

correlations with cognitive dysfunction ( 60–64 ) More recently, atrophy has been found to play

sig-nificant role in the development of cognitive difficulties in MS, perhaps particularly in patients withfrontal syndromes and more severe behavioral difficulties Atrophy also can begin very early in the

disease course ( 65 ) Frontal atrophy, supratentorial atrophy, increased third ventricle volume, and

atro-phy of the corpus callosum have been shown to correlate with a number of cognitive problems, ing problems with learning and memory, behavioral disturbance, impaired reasoning, and poor

includ-attention, as well measures of global cognitive impairment and dementia ( 65–69 ) Current research is

examining the relationships between newer imaging techniques, such as magnetization transfer ratio,proton magnetic resonance spectroscopy, and functional imaging, which also appear to be more strongly

correlated with cognitive impairment than conventional imaging ( 70 ).

Other Psychiatric Disorders

There has been some suggestion that bipolar affective disorder may occur more frequently among

patients with MS than in normal controls ( 71,72 ) However, in the more than 15 years since publication

of these findings, there have been no reported replications of these findings Psychotic symptoms arealso sometimes mentioned as being associated with MS, but there is no convincing evidence that psychotic symptoms occur at greater rates among MS patients compared with the general populationgenerally

DIAGNOSIS

As noted above, although patients with MS can show a variety of psychiatric symptoms, sion and cognitive impairment have received the greatest attention Therefore, the remainder of thischapter focuses on these two prevalent neuropsychiatric conditions

depres-Depression

To diagnose MDD, a patient must have had either depressed mood or decreased interest or pleasure

in activities (anhedonia) for at least 2 weeks, plus at least four additional symptoms including amongthe following: change in appetite, change in sleep, psychomotor retardation or agitation, fatigue, sense

of worthlessness, problems in concentration, and thoughts of suicide (see Chapter 4) Other depressive

diagnoses such as dysthymia or subthreshold depressions may include subsets of these symptoms It

is important to note that the cardinal symptoms are depressed mood or anhedonia Many depressed MS

patients may not feel sad, but may have lost motivation or interest in engaging in activities

There have been some suggestions that some symptoms of depression are confounded with

symp-toms of MS ( 73 ) For example, fatigue, cognitive impairment, insomnia, and change in weight could

all potentially be symptoms of either MDD or MS However, more recent evidence suggests that thesesymptoms may not caused by only one source, but may be multiply determined Indeed, a recent studyhas shown that all symptoms of depression improve with treatment for depression, including those

that might be confounded with MS ( 74 ) Thus, in diagnosing depression, we do not recommend

excluding symptoms of depression for a diagnosis of MDD just because they may also be related to

MS We recommend that any symptom of depression be considered a symptom of depression if it occurs

in the presence of either depressed mood or anhedonia

Depression is under diagnosed in MS ( 7 ) Estimates are that 67% of MS patients with MDD receive

no treatment for their depression ( 75 ) This is likely a result of the “don’t ask, don’t tell” rules around

depression—most patients do not tell their physicians and most physicians do not routinely ask Anumber of screening questionnaires have been shown to effectively identify MS patients who likely

have MDD ( 76 ) However, the use of screening questionnaires for depression has not been widely

adopted, in part because they require some level of organization within a clinic to have them scoredand the information presented to the provider before the visit ends

Many health care organizations, including the Veterans Affairs Administration, have adopted theuse of two questions asked by the provider annually: “have you been consistently depressed or down,most of the day, nearly every day, for the past 2 weeks?” and “in the past 2 weeks, have you been muchless interested in most things or much less able to enjoy the things you used to enjoy most of the time?”

Consistent with findings from primary care ( 77 ), these two questions very reliably identify MS patients with depression, with high rates of “hits” and low rates of false-positives ( 75 ) It is important to note that MDD requires depressed mood or anhedonia (loss of interest) We strongly urge that MS patients

be screened for depression at each visit

Cognitive Impairment

Patients are not always accurate in reporting their cognitive symptoms It is not uncommon forpatients with little or no impairment to report significant symptoms, and those with severe symptoms

to minimize the severity ( 78 ) Level of cognitive impairment cannot be inferred from physical

impair-ment as the two are not well correlated As such, formal neuropsychological assessimpair-ment performed

by a neuropsychologist is usually required for a clear and objective evaluation of level of impairmentand areas of function that are impacted If the patient is disabled because of cognitive symptoms, aneuropsychologist’s assessment may prove useful as the patient attempts to obtain appropriate dis-ability benefits Unfortunately, there are a number of potential problems associated with neuropsy-chological assessment A full battery can often take several hours to administer This can lead to anumber of difficulties, including problems related to the patient’s fatigue, issues with cost and reim-bursement, and issues of accessibility

Brief screening tools generally used by neurologists, such as the Mini-Mental State Exam, do nothave adequate sensitivity and specificity to identify probable Cognitive Disorder NOS in MS patients

In addition, this measure may misdiagnose patients who have psuedodementia resulting from severedepression, rather than cognitive dysfunction resulting from MS The most simple and accurate screen

is the report of a spouse, partner, or other family member Reports of family members have shown

much stronger correlations with objective assessment than have reports of patients ( 79 ).

CONSEQUENCES OF NEUROPSYCHIATRIC PROBLEMS

Depression has been shown to have the largest impact on quality of life in MS, exceeding the effects

of physical impairments and mobility problems ( 80 ) Depression can significantly increase disability

by reducing a person’s ability to work effectively or fulfill other social roles in the family and where In addition to reducing quality of life and engagement in significant roles, depression increases

else-the risk of suicide in MS ( 81 ) Patients with MS have been shown to be more than seven times more likely to commit suicide than the general population ( 82 ).

Cognitive impairment can also significantly reduce a patient’s ability to work or engage in dailyactivities Some research has found that cognitive impairments are the largest cause for disability,

exceeding the impact of physical impairments ( 83 ) Given the importance of cognition in the modern

workplace, this is perhaps not surprising Cognitive impairments can also impact the patient’s tionships with others People may attribute the patient’s symptoms or forgetfulness or inattention towillful behavior, rather than acknowledging the presence of cognitive difficulty Patients themselvesmay misattribute cognitive symptoms to depression, stress, aging, or “losing their minds.”

rela-Mild and moderate cognitive impairment often can require occupational accommodations,

short-term or permanent disability benefits, or unemployment ( 83,84 ), and may require additional assistance

with scheduling, organization, and other tasks More severe dementia can impair many important dailyactivities, including employment, driving, food preparation, care of small children, shopping, or man-agement of finances Patients with dementia resulting from MS may make unsafe or unwise decisions,and may be sufficiently functionally impaired to require legal conservatorship

TREATMENT

Depression

Evidence suggests that depression in MS, left untreated, will not improve ( 11 ) Although the

eti-ology of depression in MS may include disease-specific factors such as brain lesions or tion, the treatment literature has found that, as a group, patients with MS respond to treatment fordepression about as well as patients without MS

cant improvement, compared to placebo, on self-reported severity of symptoms using the Beck

Depression Inventory ( 89 ) Upon conclusion of the trial, most patients were receiving the either the

minimal clinical dosage of 150 mg per day or less A more recent study compared a 16-week

treat-ment of sertraline to two forms of psychotherapy for MDD among MS patients ( 90 ) Sertraline

pro-duced significant reductions in depressive symptoms on both objective and subjective measures ofdepression But it should be noted that physicians met every 4 weeks with patients and the mediandaily dosage by the end of treatment was 150 mg, or three times the minimum clinical dosage To thebest of our knowledge, there is no indication in the literature that there is any difference in efficacybetween sertraline and desimpramine Thus, the difference between the two trials is likely that patients

in the sertraline trial received more potent dosing, compared to those in the desimpramine trial

Physician Care for Depression

Most guidelines for the treatment of depression with pharmacotherapy, such as the Agency for HealthCare Policy and Research guidelines, require follow-up approximately every 4 weeks after the initia-tion of antidepressant medication because most medications require 4–6 weeks to achieve their full effect

( 91–94 ) The prescribing physician should monitor for response to treatment, side effects, and

adher-ence If the patient has not achieved full symptom relief, the dose should be adjusted upwards or ment should be augmented with another medication Adjustments in dose and medication should be

made to manage significant side effects Adherence, a significant problem in the treatment of sion, should be monitored closely Most patients require several times the minimal dosage to achieve

depres-full symptom relief ( 95 ).

A recent study examining the care of 260 patients with MS cared for by neurologists in a large healthmaintenance organization, found that 26% of these met MDD criteria Of those patients meeting MDDcriteria, 67% received no antidepressant, 30% received antidepressant treatment that was at threshold

or below threshold, and only 3% received doses that exceeded minimal clinical dosages ( 75 ) Data

suggests that most MS patients treated for MDD require doses greater than the minimal clinicaldosages to achieve full symptom relief These findings are highly consistent with the literature fromprimary care, which shows that physicians tend not to assess depression adequately and generally do

not provide adequate treatment ( 91 ).

There are many reasons why physicians who are not mental health specialists do not provide macotherapy that is adequate to produce full symptom relief We believe one principal reason is thatthe care models for depression do not fit with the care models in outpatient medical clinics Most neu-rologists who treat MS do not see their patients every 4 weeks, making it difficult to follow up Thus,for most clinics, alternative methods of supporting treatment for depression must be developed Anumber of studies have examined alternative methods of following depressed patients in primary careand other non-mental health specialty care clinics Most of these have used nurse telephone follow-

phar-up to monitor symptoms of depression, side effects, adherence and management of life stressors

( 96,97 ) Although such programs have not yet been developed or tested for MS, findings from other

settings suggest that depression outcomes can be significantly enhanced through such programs

Psychotherapy

There have been several studies examining the efficacy of psychotherapy for the treatment of

depression in patients with MS ( 11,90 ) The literature suggests that psychotherapies focused on

improving the coping skills of patients are just as effective as antidepressant medications.Psychotherapies that focus solely on provision of social support are less effective for patients with

MS Data from the general psychiatric literature suggest that psychotherapy and antidepressant

medi-cations results in significantly greater rates of improvement than providing either treatment alone ( 98 ).

There is no reason to believe this finding would not be true for patients with MS as well Thus, ticularly for patients with more severe depression or depression that is refractory to a single treatmentapproach, combined psychotherapy and pharmacotherapy may be indicated

par-Predictions of Response and Relapse

In general, research has not found any disease-related predictors of outcome Patients with cal and cognitive impairment appear to show initial responses to pharmaco- and psychotherapies thatare similar to those who do not have these impairments However, patients with greater lesion loadand greater levels of cognitive impairment are significantly less likely to maintain the treatment gains

physi-at 6-month follow-up ( 99 ) This suggests that MS patients with cognitive impairment and high lesion

load who are treated for depression should be followed closely to ensure maintenance of treatmentgains

Although psychotherapy and antidepressant medications produce similar results in populations ofdepressed patients, there may be some instances when one is preferable to the other Studies for thegeneral psychiatric literature indicate that antidepressant medications are more likely to be effective

than psychotherapy in patients with severe depression ( 100 ) There is also an emerging literature

sug-gesting that antidepressant medications may be less effective than psychotherapy in patients with oneclass of neuropsychological deficits, executive dysfunction (e.g., deficits in planning, organizing,sequencing, and problem solving), associated with frontal and fronto-subcortical brain lesions This

effect was first seen in the treatment of depression in the elderly ( 101–103 ) Our group has recent shown similar findings among patients with MS ( 104 ).

patients ( 106 ) and intramuscular IFN-β 1-a has been shown reduce decline across a broader number

of areas of cognitive functioning in RRMS, including processing speed, visuospatial learning and

memory, and executive functioning ( 108 ) No data on the effects of subcutaneous IFN-β 1-a on nitive functioning are currently available, and the impact of chemotherapy agents frequently used asadjuncts to the DMMs are unknown

cog-There is little data on cognitive-enhancing drugs A small open-label trial of donepezil HCl

sug-gested a limited benefit on cognition in MS ( 109 ) A small functional MRI study finds differences in

activation in left medial prefrontal areas and the right basal ganglia between cognitively intact MS

patients and controls performing a reading task following administration of rivastigmine ( 110 ) Further

research on the potential of this class of medications to slow progression of cognitive dysfunction in

MS is required before recommendations can be made

At present, the most common strategies for managing cognitive difficulties encourage the patient

to develop compensatory and accommodation strategies Neuropsychology, speech therapy, and pational therapy can be very useful in designing individualized compensation plans External memoryaids (lists and reminders), reducing distractions, and structuring tasks tend to be the most useful strate-gies, as well as pacing activity and rest periods to manage physical and cognitive fatigue Compensatingfor these kinds of difficulties frequently involves significant assistance and cooperation from others

occu-in the patient’s life

EFFECTS OF PSYCHOLOGICAL VARIABLES ON MULTIPLE SCLEROSIS

Whereas it is generally accepted that MS can have profound effects on psychological functioning inpatients, the notion that depression and/or stressful life events might affect MS is more controversial

The Effects of Stress on Multiple Sclerosis

Many patients report that stress results in disease exacerbation This notion was first considered

by Charcot, one of the earliest investigators of MS, who speculated that grief, vexation, and adverse

changes in social circumstance were related to the onset of MS ( 111 ) A recent meta-analysis of 14

empirical studies supported the hypothesis that stressful life events significantly increase the risk of

exacerbation ( 112 ) Consistent with this meta-analysis, stressors associated with the family and work

have been associated with the subsequent development of new gadolinium-enhancing MRI brain

lesions, an objective marker of inflammation ( 113 ) However, these data also suggested that different

types of stress may have differential effects Whereas most of the studies examined the effects ofcommon, often more chronic stressors, such as family or work problems, one study examined theeffects of a traumatic stressor: being an Israeli civilian under actual or threatened missile attack during

the first Persian Gulf War ( 114 ) Contrary to all other studies, these investigators found a decreased

risk of exacerbation associated with traumatic stress Given that such trauma causes a marked rise inthe release of endogenous glucocorticoids, this finding is perhaps not surprising However, it does sug-gest that if stress effects MS exacerbation then these effects may be variable depending on a number

of factors, including severity and chronicity

To date, there is considerable support for the hypothesis that stress is associated with increased risk

of exacerbation However, this literature is very underdeveloped and there is much that is unknown.The mechanisms that underlie this association are unclear and there is no conclusive evidence of acausal relationship For example, it is certainly possible that the patient’s subjective experience of stress

is an early sign of exacerbation Furthermore, we cannot link exacerbations to stressful life events in

any given individual patient Finally, it is important to acknowledge that the evidence an associationbetween stressful life events and MS exacerbation should not be interpreted as evidence that patientsare in any way responsible for exacerbations or disease progression.

Effects of Depression on Multiple Sclerosis

There are at least three potential pathways by which depression might affect MS disease:

1 Depression can affect MS indirectly by affecting behaviors such as adherence to DMMs that affect MS erbation or progression.

exac-2 Depression can affect patient’s perceptions of the severity of symptoms.

3 Depression might affect MS directly via effects on the immune system.

There is some support for the indirect hypothesis A longitudinal study of patients initiating an IFNmedication found that depression was associated with decreased adherence to medications used to treat

MS (31) However, successful treatment for depression with either psychotherapy or antidepressant medications significantly reduces risk of discontinuation of DMMs ( 115,116 ).

There is also some support for the idea that depression may increase symptom severity For ple, cross-sectional and longitudinal studies have reported that depression is associated with fatigue

exam-( 117,118 ) Treatment of depression results in significant improvements in fatigue ( 119 ) In addition,

depression has direct negative impact on performance of measures of cognitive function involvingfrontal executive systems, frontally mediated executive functions, such as working memory, timed tasks

of reasoning and problem-solving, speeded attentional processing, and planning ability It is likelythat this relationship is reciprocal in real-world scenarios, with depressed MS patients demonstratingslowed processing and making poorer choices, which leads to unwanted outcomes that further worsendepression It is currently unknown whether effective treatment for depression in MS might reducethe impact of some of these difficulties

Finally, there is also some evidence that depression may affect MS pathogenic factors IFN-γ, a

cytokine produced by T-cells, been shown both to precede and to cause MS exacerbation ( 120,121 ).

Successful treatment for depression has been shown to result in significant decreases in T-cell duction of IFN-γ ( 122 ).

pro-Table 1

Recommendations for the Treatment of Depression by Neurologists

Identify depression: Screen for depression at each visit by verbal assessment of mood and anhedonia using the

following two questions:

• “Over the past 2 weeks, have you felt down, depressed, or hopeless, more days that not?”

• “Over the past 2 weeks, have you found that you have had little interest or pleasure in doing things, more days than not?”

Explain treatment options: If a patient is depressed, explain options including antidepressant medications,

psychotherapy, or both.

If the patient selects psychotherapy: Follow-up to ensure the patient makes the appointment.

If patient agrees to initiate pharmacotherapy: Initiate treatment with a standard antidepressant medication and

follow-up at least every 4 weeks until full response is achieved.

• At each follow-up visit assess adherence and problem solve around adherence lapses.

• At each follow-up visit, adjust dose upwards or augment with additional medications if symptoms remain.

• At each follow-up visit, check for side effects Problem-solve around management of side effects Change medication or reduce dosage when management strategies fail.

Maintenance of Gains: Continue follow-up at increasingly greater intervals If patient shows significant signs

of cognitive impairment, follow the patient frequently to prevent relapse of depression.

In this chapter we have reviewed the essential empirical literature on the epidemiology, assessment,treatment, and consequences of neuropsychiatric disturbance in MS, principally depression and cog-nitive impairment Based on this literature we have made recommendations for the care of these dis-orders Table 1 displays a recommended algorithm for the treatment of depressive disorders Analgorithm for assessment and management of cognitive dysfunction is offered in Table 2

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Table 2

Recommendations for Managing Cognitive Impairment in Multiple Sclerosis

Include family members in as many patient visits as possible At each patient contact ask family member about problems with:

W Word-finding

A Attention

M Memory

M Multi-tasking

If the patient and family express no concerns:

• Monitor at future visits

If the patient expresses mild concern but family members are not concerned about.

• Consider possible mild cognitive impairment.

• Probable depression—evaluate for depression and treat.

• Consider referral for neuropsychological assessment or screening.

If the patient and family both express concern:

• This suggests probable moderate cognitive impairment and possible co-morbid depression.

• Evaluate for depression and treat.

• Initiate referral for neuropsychological evaluation.

If the family expresses concern, but patient denies concern:

• Screen for PLC, euphoria.

• Probable severe cognitive impairment and possible co-morbid depression.

• Consider possibility of dementia, initiate dementia screens.

• Initiate referral for neuropsychological evaluation if indicated.

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