Neuropsychiatric Assessment of Patients with Hyperkinetic and Hypokinetic Movement Disorders

ORIGINAL CONTRIBUTION Neuropsychiatric Assessment of Patients With Hyperkinetic and Hypokinetic Movement Disorders

Irene Litvan, MD; Jane S. Paulsen, PhD; Michael S. Mega, MD; Jeffrey L. Cummings, MD

Background: The role of the basal ganglia in neuro- years), matched for education, symptom duration, and psychiatric behaviors is not well known. Anatomical, neu- overall degree of dementia. rophysiological, and neurochemical evidence supports the notion of parallel direct and indirect basal ganglia Results: There was no difference between the groups thalamocortical motor systems, the differential involve- in the total Neuropsychiatric Inventory scores. How- ment of which accounts for the hypokinesia or hyperki- ever, there was a double dissociation in behaviors: pa- nesia observed in basal ganglia disorders. tients with HD exhibited significantly more agitation (45%), irritability (38%), and anxiety (34%), whereas Objectives: To evaluate the neuropsychiatric manifes- patients with PSP exhibited more apathy (82%) (PϽ.01). tations of patients with a hyperkinetic movement disor- Euphoria was present only in patients with HD. der, such as Huntington disease (HD), vs a hypokinetic disease, such as progressive supranuclear palsy (PSP). To Conclusions: We found that patients with HD manifested verify if patients with HD show a greater frequency of predominantly hyperactive behaviors, while those with PSP hyperactive behaviors (eg, agitation, irritation, eupho- manifested hypoactive behaviors. Based on our findings and ria, or anxiety), while those with PSP exhibit hypoac- the anatomical lesions known to occur in these disorders, tive behaviors (eg, apathy). we suggest that the hyperactive behaviors in HD are secondary to an excitatory subcortical output through the medial Patients and Methods: The Neuropsychiatric Inven- and orbitofrontal cortical circuits, while in PSP the hypo- tory, a tool with established validity and reliability, was active behaviors are secondary to hypostimulation. administered to 29 patients with HD (mean ± SD age, 43.8 ± 2 years) and 34 with PSP (mean ± SD age, 66.6 ± 1.2 Arch Neurol. 1998;55:1313-1319

UCH HAS been written kephalinergic intrinsic striatal neurons about the role of the projecting to the lateral globus pallidus and basal ganglia in mo- substantia nigra pars reticulata. This re- tor and cognitive func- sults in decreased inhibitory stimulation tions,1-7 but less is to the thalamus leading to increased ac- knownM about their role in neuropsychiat- tivity of the excitatory glutamatergic thala- ric conditions. Five frontosubcortical cir- mocortical pathway and in turn to greater cuits unite regions of the frontal lobe neuronal activity in the premotor-motor- From the Medical Neurology (supplementary motor area, frontal eye supplementary motor cortex.4 Thus, there Branch, National Institute of fields, and dorsolateral prefrontal, orbito- is overfacilitation in executing motor pro- Neurological Disorders and frontal, and anterior cingulate cortices) grams resulting in chorea. In contrast, in Stroke, National Institutes of Health, and the with the striatum, globus pallidus, and hypokinetic disorders such as Parkinson Neuropharmacology Unit, thalamus in functional systems that me- disease, there is decreased dopaminergic Defense & Veteran Head Injury diate volitional motor activity, saccadic eye nigrostriatal stimulation resulting in both Program, Henry M. Jackson movements, executive functions, social be- excess outflow of the indirect striatal path- Foundation, Bethesda, Md havior, and motivation (Figure 1).1,8-11 It way and an inhibited direct striatal path- (Dr Litvan); the Departments is hypothesized that normal basal ganglia way. Both networks increase thalamic in- of Psychiatry and Neurology, function results from a balance between hibition and decrease thalamocortical University of Iowa, Iowa City the direct and indirect striatal output path- stimulation of motor cortical areas result- (Dr Paulson); and the ways, and that differential involvement of ing in hypokinesia. A similar process oc- Departments of Neurology these pathways accounts for the hyperki- (Drs Mega and Cummings) and nesia or hypokinesia observed in disor- Psychiatry and Biobehavioral 2,4,8 Science (Dr Cummings), ders of the basal ganglia. The princi- pal abnormality in hyperkinetic disorders This article is also available on our University of California at Web site: www.ama-assn.org/neuro. Los Angeles School of Medicine, such as Huntington disease (HD) is a se- Los Angeles. lective loss of ␥-aminobutyric acid en-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 SUBJECTS AND METHODS degree of dementia using the total Mini-Mental State Ex- amination and MDRS scores (Table 1). The chorea of the patients with HD was scored accord- The subjects with HD were 29 participants in the Hunting- ing to the Unified Huntington’s Disease Rating Scale.26 The ton’s Disease Clinical Research Program at the University total chorea score, which was derived by adding all chorea of California at San Diego (Table 1). The diagnosis of HD items (ie, face, upper and lower extremities, and trunk), was was made by a senior staff neurologist on the basis of typi- used to classify the patients into 3 subgroups: those with low cal choreoid movements, family history of the disease, evi- (Ͻ12), medium (12-19), and high (Ͼ19) total chorea scores. dence of reduced caudate volume on magnetic resonance The hypokinesia of patients with PSP was scored by imaging studies (when available), and dementia accord- adding the motor items (ie, speech, limb rigidity, and neck ing to the Diagnostic and Statistical Manual of Mental Dis- rigidity) assessed using the Unified Parkinson’s Disease Rat- orders, Fourth Edition.21 ing Scale.27 The subjects with PSP consisted of 34 consecutive out- A histogram of NPI data revealed that composite scores patients (Table 1) presenting to the National Institutes of do not generate a normal distribution. Multiplying the fre- Neurological Disorders and Stroke, Bethesda, Md, for evalu- quency subscores (1-4) by the severity subscores (1-3) will ation and participation in research studies who fulfilled the not produce a 5, 7, or 11 composite score. The use of non- research criteria of the National Institutes of Neurological parametric analysis (eg, the Mann-Whitney U test) par- Disorders and Stroke–Society for Progressive Supra- tially accommodates such skewed data, but results in a loss nuclear Palsy Inc for the diagnosis of PSP.22 The diagnosis of power. Because NPI data generate a nonnormal distri- of 2 patients with PSP who subsequently died was neuro- bution, precluding traditional parametric analysis, we used pathologically confirmed using the neuropathologic crite- a bootstrap analysis.28 The program Resampling Stats (Re- ria of the National Institutes of Neurological Disorders and sampling Stats Inc, Arlington, Va) was used to evaluate sig- Stroke.23 Twenty-two of the patients with PSP were de- nificant differences among the mean composite scores of scribed previously.19 patient groups for each of the 10 NPI behaviors. Bootstrap Exclusion criteria for all subjects included history of analysis combines the raw composite scores for any given alcohol or substance abuse in the past year, head trauma behavior of the entire data set and randomly samples a num- with loss of consciousness, and psychiatric disorder(s) pre- ber of these scores equal to the number making up the ceding the onset of current disease (other than major af- groups in the data set. A mean difference composite score fective disorder, which several patients had prior to the di- is then calculated from the random samples. This is re- agnosis of HD). All participating subjects gave their consent. peated 1000 times on the data set, producing a distribu- Caregivers were interviewed with the NPI, as previously tion of possible mean difference composite scores. The ob- described.20 Briefly, screening questions for each behavior served mean differences can then be compared with this were posed first, and if a positive response was obtained distribution of the possible mean difference composite scores for any of the 10 behavioral domains, this aspect was then between the 2 clinical groups for each NPI behavior. The further explored with scripted questions. The caregiver rated probability of finding the observed mean difference based the behaviors usinga1to4scale for frequency (1, occa- on the mean difference generated by resampling is then re- sionally; 2, often; 3, frequently; and 4, very frequently) and corded. This process was repeated 10 times for each of the a 1 to 3 score for severity (1, mild; 2, moderate; and 3, 10 NPI behaviors to arrive at an average probability value marked). The composite score for each behavioral do- for each comparison. If the observed difference was greater main was the product of the frequency and severity sub- than 95% of the differences expected from random re- score for that particular behavior (maximum, 12). The to- sampling in the bootstrap method, it was judged to be sta- tal score of the NPI is the sum of the subscale scores. The tistically significant at the .05 level. Mini-Mental State Examination24 and Mattis Dementia Rat- Additional statistical tools included nonparametric ing Scale (MDRS)25 were also administered, usually on the Spearman correlation coefficient and logistic regression same day. Both patient groups were matched for overall analysis. Statistical significance was considered PϽ.05.

curs in progressive supranuclear palsy (PSP), a disease possessing contrasting motor dysfunction patterns, in which several striatal output nuclei are involved (ie, these disorders would also differ in the type of neuro- putamen, globus pallidus, and subthalamic nuclei). The psychiatric symptoms manifested. In this study, we involvement of motor and, less consistently, premotor investigated whether patients with HD manifesting cortices in PSP is attributed to subcortical nuclear de- chorea showed a higher frequency of hyperactive generation resulting in cortical underactivation.12,13 behavior (agitation, irritation, euphoria, or anxiety) Previous studies have shown that patients with hy- and whether patients with PSP with parkinsonism perkinetic (eg, HD or Tourette syndrome) and hypoki- showed a contrasting pattern with greater hypoactive netic (eg, PSP or Parkinson disease) disorders manifest behavior (apathy). We did not include depression as a neuropsychiatric disturbances (eg, apathy, depression, hypoactive behavior because depression is frequently agitation, or irritability).14-19 observed in many neurologic conditions, and we did We hypothesized that the neuropsychiatric dis- not attempt to distinguish between reactive and non- turbances exhibited by patients with basal ganglia dis- reactive depression. To test our hypothesis, we admin- orders are a consequence of a differential involvement istered the Neuropsychiatric Inventory (NPI),20 a test of the frontosubcortical circuits (Figure 1). After con- with established reliability and validity, to patients sidering the pathophysiological functioning of basal with HD and PSP matched for symptom duration and ganglia disorders, we hypothesized that in addition to overall degree of dementia.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Figure 1. Brain sections including the frontal subcortical circuits. Top, The direct and indirect frontal circuits (red arrows indicate excitatory connections and blue arrows indicate inhibitory connections). 1, Excitatory glutamatergic corticostriatal fibers. 2, Direct inhibitory ␥-aminobutyric acid (GABA)/substance P fibers (associated with D1 dopamine receptors) from the striatum to the globus pallidus interna/substantia nigra pars reticulata. 3, Indirect inhibitory

GABA/enkephalin fibers (associated with D2 dopamine receptors) from the striatum to the globus pallidus externa. 4, Indirect inhibitory GABA fibers from the globus pallidus externa to the subthalamic nucleus. 5, Indirect excitatory glutamatergic fibers from the subthalamic nucleus to the globus pallidus interna/substantia nigra pars reticulata. 6, Basal ganglia inhibitory outflow via GABA fibers from the globus pallidus interna/substantia nigra pars reticulata to specific thalamic sites. 7, Thalamic excitatory fibers returning to the cortex (shown in contralateral hemisphere for convenience). Bottom, The general segregated anatomy of the eye-movement (purple), dorsolateral (blue), orbitofrontal (green), medial frontal (red), and motor (yellow) circuits in the striatum.

RESULTS cific behavior; there was a mild (r = 0.34; PϽ.06) but not significant association between the HD subgroups clas- There were no significant differences between groups in sified according to the total chorea scores and the pres- either education or symptom duration. Age was signifi- ence of a hyperactive behavior. Moreover, patients with cantly different between the 2 patient groups (Table 1). higher chorea scores exhibited a hyperactive behavior However, a previous study found that age was not corre- more frequently (7/9 patients [78%] in the group with lated with any of the 10 studied behaviors in dementia.20 the higher chorea scores, and 5/9 [56%] in the group with Table 2 shows the mean NPI subscale scores of both pa- the middle chorea scores) than those with the lower cho- tient groups. There was no significant difference between rea scores (4/11 patients [36%] in the group with the low- the total NPI scores of the patients with HD and PSP. est chorea scores). The degree of chorea was inversely In the patients with HD, the total NPI score was associated with the total MDRS score (r = −0.46; PϽ.01), strongly influenced by irritability (r = 0.69; PϽ.001), anxi- indicating that chorea was worse in patients with a higher ety (r = 0.67; PϽ.001), disinhibition (r = 0.62; PϽ.001), degree of dementia. agitation (r = 0.59; PϽ.001), and euphoria (r = 0.53; In patients with PSP, the total NPI score was strongly PϽ.005), but less so by apathy (r = 0.37; PϽ.05). Over- associated with high apathy (r = 0.92; PϽ.001) and dis- all, patients with HD had significantly higher scores on inhibition scores (r = 0.46; PϽ.01). Anxiety was associ- agitation, anxiety, irritability, and euphoria scales, while ated with agitation (r = 0.44; PϽ.01) and symptom du- patients with PSP had higher apathy scores (Table 2). In ration (r = 0.39; PϽ.05), as previously described.19 The patients with HD, agitation was associated with anxiety total motor scores of patients with PSP were related to (r = 0.72; PϽ.001), irritability (r = 0.69; PϽ.001), dis- symptom duration (r = 0.55; PϽ.001) and inversely as- inhibition (r = 0.60; PϽ.001), and euphoria (r = 0.46; sociated with the MDRS total score (r = −0.65; PϽ.001) PϽ.01). Similarly, irritability was associated with anxi- and the Mini-Mental State Examination total score (r = ety (r = 0.88; PϽ.001), disinhibition (r = 0.64; PϽ.001), −0.52; PϽ.001). Symptom duration in PSP was also in- euphoria (r = 0.49; PϽ.01), and depression (r = 0.48; versely related to the MDRS total score (r = −0.53; PϽ.01). There was no significant association between the PϽ.005). There was no relation between total motor score degree of chorea in the patients with HD and any spe- and hypoactive behavior.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. Characteristics of Patients With Progressive Table 2. Neuropsychiatric Inventory (NPI) Supranuclear Palsy (PSP) and Huntington Disease (HD)* Composite Scores of Patients With Progressive Supranuclear Palsy (PSP) and Huntington Disease (HD)* PSP HD Characteristics (n = 34) (n = 29) PSP† HD Behavior (n = 34) (n = 29) Age, y 66.6 ± 1.2 43.8 ± 2† Sex, men/women 22/12 14/15 Apathy 6.03 ± 0.7‡ (82) 2.28 ± 0.7 (34) Education, y 14.4 ± 0.5 13.4 ± 0.4 (n = 28) Agitation 0.06 ± 0.06 (3) 1.66 ± 0.5‡ (45) Duration, y 4.5 ± 0.4 5.8 ± 0.9 (n = 28) Anxiety 0.24 ± 0.1 (12) 1.2 ± 0.3§ (34) Mini-Mental State Irritability 0.15 ± 0.09 (9) 1.31 ± 0.4‡ (38) Examination score 26 ± 0.8 24.5 ± 0.8 Disinhibition 1.79 ± 0.6 (35) 0.69 ± 0.3 (24) Mattis Dementia Dysphoria 0.5 ± 0.3 (18) 1.41 ± 0.4࿣ (41) Rating Scale score 115.6±5(n=27) 121.2 ± 3.5 (n = 28) Euphoria 0 0.93 ± 0.5࿣ (17) Delusions 0 0.66 ± 0.4 (10) *Data are expressed as mean ± SEM. Abnormal motor behavior 0.47 ± 0.4 (6) 0.41 ± 0.3 (7) †PϽ.001. Hallucinations 0 0 Total NPI score 9.23 ± 1.2 (88) 10.55 ± 1.9 (83)

Logistic regression analysis performed on the total *Data are expressed as mean ± SEM NPI composite scores (frequency of changes in percentage). The maximum composite score is 12. data set revealed that patients with HD most likely ex- †A similar pattern of NPI composite scores was found in a subset of hibited hyperactive behavior (high agitation, euphoria, patients with PSP.19 or irritability composite scores, ␹2 = 9.5; odds ratio, 7.8; ‡PϽ.001. PϽ.002), while patients with PSP most likely exhibited §PϽ.01. ࿣PϽ.05. hypoactive behavior (high apathy scale score, ␹2 = 10.9; odds ratio, 7.6; PϽ.001). resultant thalamofrontal hyperstimulation. Therefore, the COMMENT frontocortical regional cerebral blood flow in patients with HD is not reduced even when overt prefrontal-type cog- To better understand the pathophysiology of the neuro- nitive deficits are manifested, suggesting that in this dis- psychiatic behaviors observed in patients with basal gan- order a dysfunctional prefrontal cortex may be at base- glia disorders, we evaluated the behavioral disturbances line levels overstimulated by a hyperactive thalamus.39,40 of patients with HD and PSP using the same instru- Indeed, with more widespread caudate atrophy there was ments. Our study found that patients with HD more fre- higher cortical regional cerebral blood flow while the pa- quently exhibited hyperactive behaviors such as agita- tient performed a set-shifting task and a greater increase tion, irritability, euphoria, and anxiety, whereas patients of regional cerebral blood flow over baseline. The poorer with PSP more frequently displayed hypoactive behav- the performance on the task, the greater the cortical ac- ior (high levels of apathy). Previous observations tivation.39,40 At early stages in HD, when there are no fron- support this formulation. While mania, obsessive- tal lobe lesions, a relative balance between frontal and compulsive disorder, and intermittent explosive disor- increased thalamic function may explain the behavioral der are described in HD, other hyperkinetic disorders dysfunction. (ie, neuroacanthocytosis, Wilson disease, and Tourette In contrast, in patients with PSP in whom apathy is syndrome),29,30 and in patients with PD developing hy- usually present, it is hypothesized that this behavior is perkinesia,18 to the best of our knowledge they are un- the consequence of hypostimulation of the frontosub- common in untreated hypokinetic disorders. We hy- cortical circuits resulting from damage to several inte- pothesize that in HD these behaviors result from an grated nuclei (ie, in the substantia nigra, striatum, and excitatory subcortical output through the medial and or- pallidum) (Figures 2 and 3).11,41 Supportive evidence that bitofrontal circuits to the pallidum, thalamus, and cor- the frontosubcortical circuits in PSP are disconnected by tex (Figure 2 and Figure 3), in addition to the excit- prominent subcortical pathology is provided by PET mea- atory stimulation to premotor-motor and supplementary sures of glucose consumption (hypometabolism in the motor cortices, resulting in chorea. This hypothesis is sup- frontal cortex) and studies of the nigrostriatal dopamin- ported by positron emission tomography (PET) studies ergic system (decreased striatal dopamine D2 receptor up- in patients with idiopathic obsessive-compulsive disor- take ratios).42-47 However, in PSP there are also cortical der who show hyperfrontal metabolism, although con- pathologic characteristics (increased number of neuro- troversy exists about whether the increase is in the or- fibrillary tangles in the anterior cingulate cortex, ento- bitofrontal31-33 or medial frontal areas.34,35 Because the rhinal cortex, and hippocampus) that could contribute various hyperactive behaviors were significantly related to the abnormalities.12-13,48-50 in our patients with HD, it is possible that they share a Our findings suggest that in both HD and PSP, the common mechanism. There are no PET studies of HD different frontosubcortical circuits degenerate indepen- with and without hyperactive behavior, but frontal me- dently. Grouping the patients with HD according to their tabolism in HD is normal and caudate and putamen glu- degree of chorea reveals a nonsignificant association be- cose usage (where most degeneration occurs) is de- tween the severity of chorea and the presence of a hy- creased.36-38 Therefore, normal metabolism in HD may peractive behavior, but none of the individual neuropsy- result from coexistent cortical neurodegeneration and the chiatric symptoms were related to the overall chorea or

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Anterior Cingulate Cx/ Anterior Cingulate Cx/ Hippocampus/Entorhinal Cx/ Hippocampus/Entorhinal Cx/ Sup & Inf Temporal Gyri Sup & Inf Temporal Gyri

(GABA subst P) (GABA subst P)

Ventral Striatum Ventral Striatum

(GABA enk) (GABA enk)

(DA) Mediodorsal Nucleus (DA) Mediodorsal Nucleus

Globus Pallidus Externa Globus Pallidus Externa

Substantia Nigra (GABA) Substantia Nigra (GABA) (GABA) (GABA) Pars Compacta Pars Compacta

Subthalamic Nucleus Subthalamic Nucleus Ventral Pallidum Ventral Pallidum Ventral Tegmental Area Ventral Tegmental Area

Brainstem Brainstem Spinal Cord Spinal Cord

Figure 2. Schematic diagram of the hypothetical medial frontal circuit in progressive supranuclear palsy (left) and Huntington disease (right). Affected areas are shown in blue, preserved areas in gray, inhibitory neurons in yellow, and excitatory neurons in dark blue. Cx indicates cortex; sup, superior; inf, inferior; GABA, ␥-aminobutyric acid; enk, enkephalin; subst P, substance P; and DA, dopamine.

Orbitolateral Cx/ Orbitolateral Cx/ Sup & Inf Temporal Gyri/ Sup & Inf Temporal Gyri/ Anterior Cingulate Cx Anterior Cingulate Cx

(GABA subst P) (GABA subst P)

Caudate-Ventromedial Caudate-Ventromedial

(GABA enk) (GABA enk)

Ventral Anterior Nucleus Ventral Anterior Nucleus (DA) (DA) Mediodorsal Nucleus Mediodorsal Nucleus Globus Pallidus Externa Globus Pallidus Externa

Substantia Nigra (GABA) Substantia Nigra (GABA) (GABA) (GABA) Pars Compacta Pars Compacta

Subthalamic Nucleus Subthalamic Nucleus Globus Pallidus Interna (Medial Area) Globus Pallidus Interna (Medial Area) Substantia Nigra Pars Reticulata Substantia Nigra Pars Reticulata (Dorsomedial Area) (Dorsomedial Area)

Brainstem Brainstem Spinal Cord Spinal Cord

Figure 3. Schematic diagram of the hypothetical orbitofrontal circuit in progressive supranuclear palsy (left) and Huntington disease (right). Affected areas are shown in blue, preserved areas in gray, inhibitory neurons in yellow, and excitatory neurons in dark blue. Cx indicates cortex; sup, superior; inf, inferior; GABA, ␥-aminobutyric acid; enk, enkephalin; subst P, substance P; and DA, dopamine.

cognitive dysfunction scores. Motor disability in pa- suggesting that in HD, degeneration of the dorsolateral tients with HD was inversely related to the global de- and motor circuits are independent of each other, and mentia score. These findings are supported by PET and that at early stages executive cognitive dysfunction is single-photon emission computed tomographic studies largely independent of the associated motor disabil-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 ity.51,52 A similar independent circuit degeneration ap- ment disorders such as PSP, the behavioral and cogni- parently occurs in PSP. Although PSP symptom dura- tive disturbances appear to be secondary to inactivation tion was associated with global motor and cognitive of the frontal cortex or associated circuitry, whereas in impairment, there was no significant relationship be- HD, behaviors such as agitation, anxiety, and irritability tween performance on motor and executive (eg, MDRS may be related to a hyperactivated frontal cortex or cir- initiation and perseveration and verbal fluency tests) tasks. cuitry (Figures 2 and 3). Depression may be secondary Thus, it is unlikely that motor impairment can account to hypostimulation of orbitofrontal areas in both disor- for the pattern or severity of the cognitive deficits seen ders. Our study data and literature review fit most of our in PSP. In addition, there was no association between the predictions. We recognize that models of basal ganglia motor scores and NPI scores or hypoactive behavior. function are evolving and may be more complex than what Some hypoactive or hyperactive behaviors occurred we suggest.7,56,57 A better understanding of the behav- in both patient groups, suggesting that not all motor and ioral anatomy of basal ganglia disorders, which might con- behavioral neuronal circuits in these 2 basal ganglia dis- firm these models, may be achieved when these hypoth- orders degenerate independently. Considerable symptom- eses are tested using functional neuroimaging in atic overlap may be secondary to the disappearance dur- conjunction with studies of behavior. Evaluating the be- ing later disease stages of the relatively distinct anatomical havioral abnormalities of patients with movement dis- involvement observed initially. In HD, the orbitofrontal orders may not only help clarify the role of the basal gan- and anterior cingulate cortices, ventromedial caudate, and glia in behavior but ultimately benefit patient care. subthalamic nuclei are affected to differing degrees de- pending on the stage of the disease. Lesions are thought Accepted for publication March 18, 1998. to progress from medial to lateral and from dorsal to ven- This study was supported by grant AG10123 from the tral caudate, possibly impacting the orbital and dorsolat- National Institute on Aging Alzheimer’s Disease Center, eral circuits before the cingulate circuit. Bethesda, Md, and the Katherine and Benjamin Kagin Re- Depression was present in 41% of our patients with search Program, Los Angeles, Calif. HD. Fludeoxyglucose F 18–PET studies in patients with Reprints: Irene Litvan, MD, National Institutes of Neu- HD with and without depression showed greater orbi- rological Disorders and Stroke, National Institutes of Health, tofrontal and thalamic hypometabolism in those with Federal Bldg, Room 714, Bethesda, MD 20892-9130 (e- mood abnormalities.53 It is possible that in patients with mail: [email protected]). HD with depression, the thalamo-orbitofrontal hypometabolism, in addition to the hypothesized thalamofron- REFERENCES tal hyperfunction described earlier, could yield an overall normal scan. Depression was less frequent (18%) in 1. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally seg- patients with PSP than in those with HD. In our study, regated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9: symptom duration was unrelated to either euphoria or 357-381. depression. We expected that mania or obsessive- 2. DeLong MR. 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Call for Papers

Neuro-Oncology 1999

The ARCHIVES is planning a theme approach to neuro-oncology for the April 1999 issue. Papers are requested for consideration that represent new and important information related to brain tumors. Both clinical and basic science subjects are requested. Manuscripts must be received prior to November 1 to allow for appropriate consideration.

Roger N. Rosenberg, MD Editor

ARCH NEUROL / VOL 55, OCT 1998 1319

ritical illness myopathy is a poorly understood, but increasingly recognized clinical syndrome that C characteristically occurs in the intensive care unit among patients who have been treated with multiple drugs (particularly neuromuscular-blocking agents and antibi- otics) and high-dose steroids.1-6 This rapidly progressive myopathy is characterized by muscle fiber atrophy and/or ne- crosis, often selectively affecting type 2 myofibers (Figure). Steroids are potent inducers of some forms of cytochrome P450.7 Recent studies8 suggest that cytochrome P450 is associated with skeletal muscle sarcoplasmic reticulum. In- Muscle biopsy section from a 66-year-old woman with critical illness duction of cytochrome P450 and the consequent formation myopathy demonstrating severe type 2 myofiber atrophy and similar-stage of reactive intermediates in the metabolism of some com- regeneration consistent with a monophasic toxic myopathy preferentially pounds result in the activation of calcium-release channels.9 affecting type 2 muscle fibers (frozen section, hematoxylin-eosin, ϫ400). Critical illness myopathy may result from steroid induction of cytochrome P450 associated with sarcoplasmic reticu- 1. Chad DA, Laconis D. Critically ill patients with newly acquired weakness: the lum. The consequent production of reactive intermediate clinicopathological spectrum. Ann Neurol. 1994;35:257-259. metabolites of other drugs given in the setting of critical ill- 2. Al-Lonzi MT, Pestronk A, Yee WC, Flaris N, Cooper J. Rapidly evolving myopathy ness then causes pathologic activation of calcium-release with myosin-deficient muscle fibers. Ann Neurol. 1994;35:273-279. 3. Ruff RL. Acute illness myopathy. Neurology. 1996;46:600-601. channels in sarcoplasmic reticulum and consequent muscle 4. Rich MM, Teener JW, Raps EC, Schotland DL, Bird SJ. Muscle is electrically injury. The differences between muscle fiber types in inexcitable in acute quadriplegic myopathy. Neurology. 1996;46:731-736. calcium handling may account for the preferential 5. Gutmann L, Blumenthal D, Gutmann L, Schochet SS. Acute type II myofiber atrophy in critical illness. Neurology. 1996;46:819-821. involvement of type 2 muscle fibers in both steroid 6. Faragher MK, Day BJ, Dennett X. Critical care myopathy: an electrophysi- myopathy8 and critical illness myopathy. ological and histological study. Muscle Nerve. 1996;19:516-518. 7. Nebert DW, Adesnik M, Coon MJ, et al. The P450 gene superfamily: recom- mended nomemclature. DNA. 1987;6:1-11. Jack E. Riggs, MD 8. Crosbie SJ, Blain PG, Williams FM. An investigation into the role of rat skel- Sydney S. Schochet, Jr, MD etal muscle as a site for xenobiotic metabolism using microsomes and iso- Departments of Neurology and Pathology lated cells. Hum Exp Toxicol. 1997;16:138-145. 9. Stoyanovsky DA, Cederbaum AI. Thiol oxidation and cytochrome P450- West Virginia University Health Sciences Center 2+ dependent metabolism of CCl4 trigers Ca release from liver microsomes. Bio- Morgantown, WV 26506-9180 chemistry. 1996;35:15839-15845.

Correction Correction

Error in Figure. In the article titled “Neuropsychiatric As- sessment of Patients With Hyperkinetic and Hypokinetic Movement Disorders” by Litvan et al published in the Oc- tober 1998 issue of the ARCHIVES (1998;55:1313-1319), the red arrows showing inhibitory neurons on figures 2 and 3 should have been yellow, as indicated in the figure legend.

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