CASE REPORT
Unilateral Perseverationnnn Lealani Mae Y. Acosta, MD,* Ira J. Goodman, MD,wz and Kenneth M. Heilman, MDy8
Abstract: The brain’s action-intentional (“when”) programming system helps to control when to and when not to initiate an action, when to persist at an action, and when to terminate an action. Motor perseveration is a failure to terminate an action. This disengagement disorder most often results from dysfunction of the executive frontal-subcortical networks that control the action-intentional programming system. Reports of unilateral perseveration are unusual. Here we describe a patient with a form of progressive supranuclear palsy (PSP) who exhibited continuous right-hand motor perseveration. This 68-year-old right-handed man had impaired walking and vertical gaze, consistent with PSP. He often repeated words, and on many motor tasks he showed continuous perseveration of his right but not his left hand. Unilateral motor perseveration may be a sign of PSP, the corticobasal syndrome, or a subtype of these disorders. Future studies of patients with both disorders should use tasks that assess for asymmetric hand perseveration. The mechanism of the unilateral perseveration must also be determined. Bilateral perseveration is found most often in patients with unilateral right frontal-subcortical (basal ganglia) or insula dysfunction. Because patients with PSP or corticobasal syndrome have callosal degeneration, their unilateral perseveration might result from a callosal disconnection of the right frontal lobe from the left hemisphere’s premotor and motor as well as speech areas. Key Words: unilateral perseveration, progressive supranuclear palsy, corticobasal degeneration, corpus callosum, parkinsonism (Cogn Behav Neurol 2013;26:181–188)
Reader Benefit: Testing for and observing unilateral perseveration may aid in the diagnosis of progressive supranuclear palsy and corticobasal syndrome, and in the recognition of their associated disabilities. Received for publication September 24, 2012; accepted November 15, 2013. From the *Department of Neurology, Vanderbilt University, Nashville, TN; wThe Compass Clinic, Orlando, FL; zDepartment of Neurology, University of Central Florida College of Medicine, Orlando, FL; yDepartment of Neurology, University of Florida College of Medicine, Gainesville, FL; and 8The Malcom Randall Veterans Affairs Medical Center, Gainesville, FL. Supported in part by the State of Florida Memory Clinics. The authors declare no conflicts of interest. Reprints: Lealani Mae Y. Acosta, MD, Vanderbilt University Medical Center, Department of Neurology, A-0118 Medical Center North, Nashville, TN 37232-2551 (e-mail: lealani.mae.acosta@vanderbilt. edu). Copyright r 2013 by Lippincott Williams & Wilkins
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CBS = corticobasal syndrome; MRI = magnetic imaging; PSP = progressive supranuclear palsy.
resonance
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rogressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) often overlap clinically, pathologically, and genetically, sharing tau haplotypes and mutations (Kertesz and McMonagle, 2010). Many patients with overlapping PSP-CBS syndrome demonstrate asymmetric signs of an ideomotor apraxia, with a failure of knowing “how” to move their hands (Jacobs et al, 1999). When patients with this disorder perform purposeful skilled actions, they make asymmetric postural, spatial, and temporal movement errors. These patients may also exhibit limb-kinetic apraxia (Zadikoff and Lang, 2005), an impairment of the ability to make independent, precise, and coordinated finger movements. Many patients with apraxic “how” disorders also have impairments of the action-intentional (“when”) system, such as impairments of knowing “when” to initiate an action, including akinesia and hypokinesia (eg, slowed reaction times; Caselli et al, 1999); when not to initiate an action (defective response inhibition); and motor impersistence, a deficit in when to persist. A fourth action-intention (when) disorder is perseveration. Until now, asymmetric perseveration has not been described in PSP-CBS syndrome. Perseveration, “the incorrect repetition of a previous response,” can be manifest as either a cognitive or a motor disorder (Heilman et al, 2008). Luria (1965) described 2 subtypes: “efferent perseveration” and “inertia of a previously recorded programme of action.” Efferent perseveration appears as compulsive repetition, while “inertia” is the individual’s being stuck in a pattern of action, unable to switch to another. Sandson and Albert (1984, 1987) divided perseveration into 3 subtypes. In their “stuck in set” subtype, as in Luria’s “inertia,” the person continues a cognitive strategy to solve a problem when a new strategy is needed. In what the authors termed “recurrent perseveration,” the patient repeats an earlier response when given a different stimulus. “Continuous” perseveration” is similar to Luria’s “efferent” subtype in that the patient continues to repeat the same action or behavior without interruption. Typically, perseveration is considered to be induced dysfunction of the frontal lobes (Na et al, 1999; Sandson and Albert, 1984, 1987; Vilkki, 1989) as related to the intentional “when” systems, such as when to start an activity, when not to start, when to continue, and when to stop (Heilman et al, 2008). The network that mediates intention includes the frontal lobes, which project to the www.cogbehavneurol.com |
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striatum; the striatum, projecting to the globus pallidus pars interna or the substantia nigra pars reticulata, which then project to the thalamic nuclei; and finally back to the frontal cortex (Heilman et al, 2008). Perseverative behaviors have been noted in patients with disorders of the basal ganglia networks, including stroke (Nys et al, 2006) and degenerative conditions such as Parkinson disease (Taylor et al, 1986). Animal studies have also found perseverative behavior resulting from temporal-parietal lesions (Denny-Brown and Chambers, 1958). In terms of hemispheric laterality, recurrent perseveration is more often associated with injury to the right than the left hemisphere (Na et al, 1999; Pia et al, 2009). However, Sandson and Albert (1987) found that when patients made drawings on command, some of those with left hemisphere damage and aphasia demonstrated recurrent perseveration. These researchers also reported that continuous perseveration was more often associated with right than with left hemisphere lesions. Because previous studies did not precisely document whether the investigators used only 1 or both of the patients’ hands to test tasks of perseveration, it is difficult to determine whether the disorder was unilateral or bilateral. Still, a few reports have commented specifically on testing that used both of the participants’ hands and found deficits in their performance, indicating bilateral perseverative errors (Kimura, 1977; Ruchinskas and Giuliano, 2003). Fung et al (1997) described patients with clonic perseveration after thalamic or basal ganglia strokes, and noted that the perseverative movements were bilateral, though usually worse on 1 side than the other. Unilateral perseveration has been reported in association with unilateral neglect, although most of the patients were tested only with their dominant hand (Na et al, 1999; Pia et al, 2009; Ronchi et al, 2009; Rusconi et al, 2002). Many of these patients had recurrent or continuous perseveration (Guerrero et al, 2010; Kim et al, 2009). We found only 1 case report (Shahani et al, 1970) in which unilateral perseveration was observed in a patient who also had a strong ipsilateral grasp reflex secondary to a left hemisphere stroke induced by a pericallosal artery occlusion. In our clinic, we studied a patient with probable PSP or CBS who had a profound and disabling continuous perseverative disorder of his right hand. Here we describe this patient and his abnormal perseverative behaviors, and discuss some possible mechanisms of his disorder.
handwriting had become more “jumbled” over time, to the point of illegibility. His personality had changed. He became less interested in initiating activities that he had formerly enjoyed. He became less able to solve problems. When doing chores around the house, he became compulsive, wanting to clean things very thoroughly, but not always doing an effective job. The patient was seen by his local neurologist, who suspected PSP and sent him to our clinic for further evaluation. We evaluated the patient’s cognitive and motor abilities (Table 1). We will discuss his results throughout the case history. On the Mini-Mental State Examination (Folstein et al, 1975), he scored 26 out of 30 points. He lost 1 point each for not knowing the day of the month and for missing 1 iteration of the serial 7’s. He lost the other 2 points because he was unable to write a sentence and copy the design. These latter 2 deficits were not linguisticcognitive, but rather were secondary to his impaired control of motor output. When using his right hand to write the sentence for the Mini-Mental State Examination, he added extra lines within letters and he drew tight squiggles that looked as though he was crossing something out (Figure 1). When he wrote individual letters in response to dictation, his writing with his right hand showed the same extra lines and squiggles (Figure 2A). By contrast, when he wrote
CASE REPORT A 68-year-old right-handed college-educated man had a 2-year history of problems with walking. His family said that overall he had been much slower than usual in both walking and talking. He often lost his balance while walking, usually falling backwards; several weeks before we evaluated him, he had fallen and broken his hip. His
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TABLE 1. This Patient’s Motor and Cognitive Assessment Test
Result
Mini-Mental State Examination1 Fist-edge-palm3 Crossed response inhibition3 Go/No Go3 3
Hand alternation Ideomotor apraxia4
Limb-kinetic apraxia4
Boston Naming Test short form6 Digit span4 Letter fluency4 Category fluency4
26/30; corrected for age and education level: 25/30.2 Preserved orientation to place, naming, repetition, reading, and following commands Impaired bilaterally: unable to achieve after 5 attempts. Perseveration noted in right hand only Normal: 8 of 10 trials correct Impaired bilaterally: 7 of 10 trials incorrect. Perseveration noted in right hand only Normal Impaired bilateral ability to pantomime how to use scissors and whisk eggs. Intact ability to pantomime the use of a hammer and a screwdriver Impaired bilaterally. Time to complete 30 rotations of a nickel using thumb, middle, and forefinger of left hand = 47.8 seconds, right hand = 43.7 seconds. This is equivalent to 31.86 seconds for 20 rotations with the left hand (normal = 14.5 seconds) and 29.1 seconds for the right hand (normal = 13.2 seconds)5 Normal: 14 of 15 correct Normal: 6 digits forward, 3 backward Impaired letter fluency: F/A/S: 4/4/7 Impaired category fluency with 6 animals: 6
1, Folstein et al, 1975. 2, Mungas et al, 1996. 3, Luria, 1966. 4, Doty et al, 1990. 5, Mendoza et al, 2009. 6, Kaplan et al, 1983.
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FIGURE 1. As part of the Mini-Mental State Examination (Folstein et al, 1975), the patient writes a sentence with his right hand. He perseverates, repeating lines within letters and spontaneously writing squiggles.
letters with his left (nondominant) hand, he did not add extra lines (Figure 2B). He showed the same pattern of perseveration when he performed Luria’s alternating graphical sequence test, the “rampart” design drawing test (Luria, 1966). The examiner drew 2 rampart designs and asked the patient to copy the design beneath, with his left hand (Figure 3A)
FIGURE 2. The patient writes individual letters in response to dictation. Panel A: When he writes with his right hand, he shows continuous perseveration. He also has “stuck in set” perseveration: Each character, while illegible, looks similar to the character above it. Panel B: When he writes with his left hand, his letters are individually recognizable and have few extra lines. r
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and his right hand (Figure 3B). Unlike his clean left hand drawing, his right hand drawing again has extra lines and squiggles. The pattern of right-hand perseveration continued in his drawings of the interlocking pentagons given in the Mini-Mental State Examination (Figure 4A). With his right hand, he drew extra lines over the sides of the pentagons (Figure 4B). The drawing that he made with his left hand is much cleaner (Figure 4C). When we assessed the patient for frontal lobe dysfunction (Table 1), we asked him to perform some of the other Luria tasks (Luria, 1966). As with his writing and drawing, he showed severe continuous perseveration of his right hand. For example, we noted the same error when having him perform the “fist-edge-palm” hand sequencing task. In this test, the seated examiner asks the patient to watch her make a sequence of movements and then to perform the same movements. Here is the sequence: With 1 hand, the examiner makes a fist and puts it on her lap. Then she lifts her fist from her lap, opens her hand, and puts the ulnar portion of her open hand on her lap. Then she again lifts her hand, rotates her arm, and puts the palm of her hand on her lap. The examiner usually repeats the sequence of movements 3 times. Then she asks the patient to perform the same sequence with 1 hand and then with the other hand. All 5 times that our patient tried the task with his right hand, he made the first fist-to-lap movement but perseverated on it and never progressed to any of the other movements (Table 1). He did not perseverate when he tried the task with his left hand. We gave the patient a frontal-motor test for echopraxia in which we asked him to tap his hand twice after the examiner had tapped once, and to tap once after the examiner had tapped twice. When he performed the task using his right hand, he would keep tapping his right hand for several seconds, but when he used his left hand, he performed the task without error. When we asked the patient to switch tasks from drawing the interlocking pentagons with his right hand to drawing the Luria ramparts with his right hand, he did not have recurrent perseveration. We gave the patient the crossed response inhibition test (Table 1) (Luria, 1966). In this test, the examiner asks seated patients to close their eyes and put both of their www.cogbehavneurol.com |
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FIGURE 3. For Luria’s (1966) alternating graphical sequence test, the “ramparts” design, the patient is asked to copy a design beneath the example that the examiner has drawn on the page. Panel A: Drawing with his left hand, the patient draws the design cleanly. Panel B: Drawing with his right hand, the patient perseverates, with extra lines and squiggles.
palms on their lap. The examiner explains that she will touch the back of 1 of the patients’ hands, and when she does so, the patients should raise their other hand. This is the “crossed response.” If patients raise the hand touched rather than the opposite hand, it is considered an error. Our patient performed normally on the crossed response task.
We gave him the hand alternation test (Luria, 1966). In this test, patients put both hands on their lap. They watch the examiner perform the task and then try it themselves. They are asked to flex the fingers of 1 hand and make a fist; they are to hold the other hand open with the fingers extended. Then they are asked to switch these
FIGURE 4. In the Mini-Mental State Examination (Folstein et al, 1975), the patient copies interlocking pentagons from the original (Panel A). He perseverates when drawing with his right hand (Panel B), but not his left hand (Panel C).
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postures repeatedly between their hands. Our patient also performed normally on this hand alternation test. On the Hopkins Verbal Learning Test (Brandt, 1991) and other recall tasks, he often repeated the words spoken by the examiner (echolalia). He also demonstrated bilateral ideomotor and limb-kinetic apraxia of his hands (Table 1). He showed neither apraxia of speech nor a nonfluent aphasia. He scored normally on the Hopkins Verbal Learning Test (with a retention of 85%), the Boston Naming Test (Kaplan et al, 1983), and digit span (Table 1). His letter and category fluency scores showed impairment (Table 1). He did not display any left-right confusion. As for the rest of his neurologic examination, cranial nerve testing showed that his pupils were equally round and reactive to light. He had full visual fields, and no evidence of visual inattention or extinction. Testing of his extraocular movements revealed that both eyes had a limitation of vertical (up and down) saccades as well as pursuit. He had a positive oculocephalic reflex, with passive movement of the head in all directions. Facial sensation was intact. He had a mask-like face with an abnormally low spontaneous blink rate. His speech was hypophonic. He tended to repeat words even during conversation (echolalia). The motor examination revealed increased tone (plastic rigidity) in his neck, but normal tone and strength in all his limbs. Because of his recent hip fracture, we tested his right leg cautiously. He had bradykinesia and hypokinesia in both of his arms and hands. He also had tactile mitgehen of both hands: The examiner told him to put his hands on his lap and keep his arms and hands relaxed. Then the examiner touched him lightly on his fingertips. As she tried to move her hand away, the patient moved his hand to keep his finger in contact with her finger (Fitzgerald et al, 2007). We tested the patient for an “avoidance response.” He held his hand supine and fully relaxed, with his fingers hanging down. The examiner rubbed her forefinger against the patient’s palm and then out to the tips of his fingers. During this stimulation, the patient extended his fingers. This was an avoidance response, which is abnormal and evidence of parietal dysfunction (DennyBrown and Chambers, 1958). His avoidance response was mild, but greater in his left hand than his right. His reflexes were symmetric and he had bilateral palmar grasp. His plantar response was extensor in both feet. The sensory examination was normal, without evidence of inattention or extinction. We could not evaluate the patient’s gait because of his hip fracture. Magnetic resonance imaging (MRI) of the patient’s brain (Figure 5) disclosed mesencephalic atrophy consistent with the “hummingbird sign,” which is seen in many patients with PSP. The characteristic midsagittal MRI image of midbrain atrophy without pontine atrophy looks like a hummingbird (Graber and Staudinger, 2009). The patient’s scan did not show lateralized cortical atrophy or any abnormality in the corpus callosum. r
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FIGURE 5. Magnetic resonance imaging scan of the patient’s brain. This midsagittal fluid attenuated inversion recovery section shows the classic midbrain atrophy (“hummingbird sign”) of progressive supranuclear palsy.
A positron emission tomogram obtained by the patient’s original consulting neurologist showed subtle bilateral frontal and temporal reductions of activity, without indication of lateralized changes. On a follow-up examination 12 months after admission, the patient’s symptoms had not changed markedly from his original presentation.
DISCUSSION As originally described by Steele et al (1964), PSP has as its classic hallmark a supranuclear ophthalmoplegia, primarily affecting vertical gaze. Patients also have pseudobulbar palsy, axial dystonias, and evidence of frontal-subcortical cognitive dysfunction (Albert et al, 1974), with characteristic midbrain atrophy seen on imaging (Jankovic, 2012). As noted by Kouri et al (2011), patients with CBS can present with several different syndromes. Parkinson disease and some of the parkinsonian spectrum disorders, such as CBS, commonly affect 1 side of the body more than the other. In contrast, PSP of the Richardson type (“PSP-R”) (Williams et al, 2005) typically affects both sides of the body almost equally. Our patient’s clinical history, cognitive testing, and elements of his neurologic examination were consistent with a diagnosis of PSP, and his brain MRI revealed the classic mesencephalic atrophy of PSP. Patients with CBS can also manifest parkinsonian signs and dementia, in contrast to patients with the Richardson type of PSP (Williams et al, 2005); however, many patients with CBS www.cogbehavneurol.com |
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have asymmetric signs, as did our patient. Patients with CBS can have an asymmetric alien limb; while our patient did not reveal a classic CBS alien limb, he had an asymmetric avoidance response that may have been the first sign of alien limb. Many patients with CBS have either an asymmetric ideomotor or limb-kinetic apraxia; while our patient did have both of these forms of apraxia, he had no limb asymmetry. While the typical syndromes of PSP and CBS are distinct, many patients, like ours, have an atypical PSP-CBS syndrome with overlapping clinical features. Unlike previously reported patients with PSP or CBS, our patient demonstrated continuous unilateral hand motor perseveration. However, other than his perseveration when using his right hand, he did not have asymmetric motor signs. It is possible that his asymmetric perseveration was a sign of further dysfunction of his right hemibody. While, as mentioned, CBS is often characterized by asymmetric rigidity, asymmetric apraxia, cortical sensory deficits, and myoclonus, some patients do not develop these features, but instead have features consistent with the Richardson form of PSP. They present with postural instability, falling, and a vertical supranuclear gaze palsy, as did our patient. Unlike patients with a second form of PSP, called the parkinsonian form, our patient did not have a tremor or asymmetric parkinsonian signs. The pathophysiology of our patient’s unilateral perseveration is not known, but there are several possibilities. Because his perseveration was primarily of his right hand, it is likely that the locus of the dysfunction was within his left hemisphere. Ronchi et al (2012) studied the perseveration errors observed during a cancellation task in patients with neglect, and found that these errors were most often associated with lesions of the insula. Whitwell and colleagues (2010) reported that patients with CBS had atrophy of the insula. Although we did not see any asymmetric atrophy of our patient’s insula, it is possible that atrophy of this region contributed to his unilateral motor perseveration. Stoffers et al (2001) suggested that perseveration may be an early indicator of Parkinson disease and related to basal ganglia dysfunction. Thus, another possible cause of our patient’s unilateral continuous perseveration may be related to basal ganglia dysfunction. Right hemisphere lesions can be associated with continuous perseveration of both the left and right hands. Nys and coworkers (2006) reported that damage to the caudate nucleus was an important correlate of perseveration, independent of whether patients showed hemineglect. Pia and colleagues (2009) concluded that perseverative errors were associated with right basal ganglia lesions. Studies of patients with CBS have shown that they may have atrophy of the head of the caudate (Su¨dmeyer et al, 2012). Therefore, it is possible that asymmetric degeneration of the head of the caudate, which is strongly connected with the frontal lobes, may have played an important role in our patient’s unilateral perseverative behavior. Kleinman and colleagues (2013) also studied motor perseveration in patients with right hemispheric strokes,
including patients who did not show neglect. The authors found that the lesion most commonly associated with motor perseveration was injury to the right dorsolateral frontal lobe. Unlike Nys et al (2006), Kleinman et al (2013) did not find that caudate injury was related to perseveration. However, the dorsolateral frontal lobes are known to have strong connections with the caudate (Leh et al, 2007). Kouri and colleagues (2011) reported that atrophy of the anterior corpus callosum is a potential marker to differentiate CBS from the Richardson form of PSP. As mentioned, the continuous motor perseveration of our patient’s right hand and his propensity to repeat words suggest that the cause was his left hemisphere dysfunction. Although we do not know the locus or loci of the responsible left hemisphere dysfunction, in light of Kouri et al’s (2011) report it is possible that the mechanism of his perseveration was a partial callosal disconnection. Our patient did not show evidence of callosal disconnection, such as hemi-alexia or extinction to bilateral simultaneous stimulation. These signs, however, are often associated with posterior callosal dysfunction. One of the best signs of injury to the anterior corpus callosum is ideomotor apraxia of the left hand. Our patient did have ideomotor apraxia of his left hand, but he also had apraxia of his right hand. Thus, we cannot know if his left hand apraxia was related to a callosal disconnection, left hemispheric dysfunction, or even bilateral hemispheric dysfunction. Although our patient’s MRI did not show overt evidence of a corpus callosum abnormality, his clinical changes could potentially precede any appreciable radiographic evidence. We also note that he underwent a routine protocol MRI as part of a dementia work-up. More detailed imaging, such as with tractography, might have highlighted subtler differences than were visualized on his scan. Further laboratory tests such as electroencephalography and single-photon emission computed tomography might also have helped to determine if he had any other asymmetric patterns of brain activity. As mentioned, the 1 case report that we unearthed commenting on unilateral perseveration and grasp reflex (Shahani et al, 1970) reported the disorders to be secondary to a pericallosal artery occlusion, further implicating callosal damage. Several studies have shown that right hemisphere dysfunction can be associated with bilateral perseveration (Kleinman et al, 2013; Pia et al, 2009; Sandson and Albert, 1987). The finding that patients with right lateral frontal lobe or caudate injury have bilateral motor perseveration suggests that normally the network formed by the right frontal lobe and caudate plays a critical role in determining when an action should be terminated. Because the right hand is controlled by the left premotor and motor cortex and the right frontal lobe is important in terminating activity, the right frontal lobe must communicate with the left hemisphere’s motor areas, and this
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communication most likely occurs through the corpus callosum. Thus, if the right hemisphere is intact but the corpus callosum is injured, then the left hand will not exhibit motor perseveration. But the right hand, being disconnected from the right frontal lobe, may exhibit motor perseveration. Sine et al (1984) reported a patient who had a “full callosal syndrome,” with perseveration on 1 side of the body, specifically when doing spatial tasks with the right hand and doing symbolic tasks with the left hand. For example, when copying a flower with the right hand, the patient would perseverate and draw the petals numerous times. In contrast, the left hand appeared to be “stuck in set”: After the patient drew a clock face, he was asked to write his name, but he again began to write the numbers of a clock. Sweet (1941) reported a patient who had an aneurysm of the left anterior cerebral artery that led to softening and destruction of parts of the corpus callosum. Although not discussed by Sweet, when we reviewed his report and his patient’s writing sample, we saw that she perseverated when she wrote with her right hand. For example, when she tried to write “Chicago,” she wrote, “Chicacaqo,” perseverating on the “ca.” This observation suggests that corpus callosum injury, even with sparing of the frontal lobes, basal ganglia, and insula, can lead to perseveration. Future studies of patients with CBS or the parkinsonian or Richardson form of PSP, assessing each hand independently with tests like Luria’s fist-edge-palm, may let us learn if any of these diseases are associated with asymmetric hand perseveration. It is also possible that our patient had a form of a parkinsonian spectrum disorder that has not yet been described and that might be called perseverative progressive supranuclear palsy. Further studies of the neuropathology of our patient or other patients with the same disorder may also help us understand its relationship to other parkinsonian spectrum disorders.
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Sine RD, Soufi A, Shah M. 1984. Callosal syndrome: implications for understanding the neuropsychology of stroke. Arch Phys Med Rehabil. 65:606–610. Steele JC, Richardson JC, Olszewski J. 1964. Progressive supranuclear palsy. Arch Neurol. 10:333–359. Stoffers D, Berendse HW, Deijen JB, et al. 2001. Motor perseveration is an early sign of Parkinson’s disease. Neurology. 57:2111–2113. Su¨dmeyer M, Pieperhoff P, Ferrea S, et al. 2012. Longitudinal deformation-based morphometry reveals spatio-temporal dynamics of brain volume changes in patients with corticobasal syndrome. PLoS One. 7:e41873. Sweet W. 1941. Seeping intracranial aneurysm simulating neoplasm: syndrome of the corpus callosum. Arch Neurol Psychiatry. 45:86–104.
Taylor AE, Saint-Cyr JA, Lang AE. 1986. Frontal lobe dysfunction in Parkinson’s disease: the cortical focus of neostriatal outflow. Brain. 109:845–883. Vilkki J. 1989. Perseveration in memory for figures after frontal lobe lesions. Neuropsychologia. 27:1101–1104. Whitwell JL, Jack CR Jr, Boeve BF, et al. 2010. Imaging correlates of pathology in corticobasal syndrome. Neurology. 75: 1879–1887. Williams DR, de Silva R, Paviour DC, et al. 2005. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain. 128:1247–1258. Zadikoff C, Lang AE. 2005. Apraxia in movement disorders. Brain. 128:1480–1497.
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Unilateral Perseverationnnn Lealani Mae Y. Acosta, MD,* Ira J. Goodman, MD,wz and Kenneth M. Heilman, MDy8
Abstract: The brain’s action-intentional (“when”) programming system helps to control when to and when not to initiate an action, when to persist at an action, and when to terminate an action. Motor perseveration is a failure to terminate an action. This disengagement disorder most often results from dysfunction of the executive frontal-subcortical networks that control the action-intentional programming system. Reports of unilateral perseveration are unusual. Here we describe a patient with a form of progressive supranuclear palsy (PSP) who exhibited continuous right-hand motor perseveration. This 68-year-old right-handed man had impaired walking and vertical gaze, consistent with PSP. He often repeated words, and on many motor tasks he showed continuous perseveration of his right but not his left hand. Unilateral motor perseveration may be a sign of PSP, the corticobasal syndrome, or a subtype of these disorders. Future studies of patients with both disorders should use tasks that assess for asymmetric hand perseveration. The mechanism of the unilateral perseveration must also be determined. Bilateral perseveration is found most often in patients with unilateral right frontal-subcortical (basal ganglia) or insula dysfunction. Because patients with PSP or corticobasal syndrome have callosal degeneration, their unilateral perseveration might result from a callosal disconnection of the right frontal lobe from the left hemisphere’s premotor and motor as well as speech areas. Key Words: unilateral perseveration, progressive supranuclear palsy, corticobasal degeneration, corpus callosum, parkinsonism (Cogn Behav Neurol 2013;26:181–188)
Reader Benefit: Testing for and observing unilateral perseveration may aid in the diagnosis of progressive supranuclear palsy and corticobasal syndrome, and in the recognition of their associated disabilities. Received for publication September 24, 2012; accepted November 15, 2013. From the *Department of Neurology, Vanderbilt University, Nashville, TN; wThe Compass Clinic, Orlando, FL; zDepartment of Neurology, University of Central Florida College of Medicine, Orlando, FL; yDepartment of Neurology, University of Florida College of Medicine, Gainesville, FL; and 8The Malcom Randall Veterans Affairs Medical Center, Gainesville, FL. Supported in part by the State of Florida Memory Clinics. The authors declare no conflicts of interest. Reprints: Lealani Mae Y. Acosta, MD, Vanderbilt University Medical Center, Department of Neurology, A-0118 Medical Center North, Nashville, TN 37232-2551 (e-mail: lealani.mae.acosta@vanderbilt. edu). Copyright r 2013 by Lippincott Williams & Wilkins
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CBS = corticobasal syndrome; MRI = magnetic imaging; PSP = progressive supranuclear palsy.
resonance
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rogressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) often overlap clinically, pathologically, and genetically, sharing tau haplotypes and mutations (Kertesz and McMonagle, 2010). Many patients with overlapping PSP-CBS syndrome demonstrate asymmetric signs of an ideomotor apraxia, with a failure of knowing “how” to move their hands (Jacobs et al, 1999). When patients with this disorder perform purposeful skilled actions, they make asymmetric postural, spatial, and temporal movement errors. These patients may also exhibit limb-kinetic apraxia (Zadikoff and Lang, 2005), an impairment of the ability to make independent, precise, and coordinated finger movements. Many patients with apraxic “how” disorders also have impairments of the action-intentional (“when”) system, such as impairments of knowing “when” to initiate an action, including akinesia and hypokinesia (eg, slowed reaction times; Caselli et al, 1999); when not to initiate an action (defective response inhibition); and motor impersistence, a deficit in when to persist. A fourth action-intention (when) disorder is perseveration. Until now, asymmetric perseveration has not been described in PSP-CBS syndrome. Perseveration, “the incorrect repetition of a previous response,” can be manifest as either a cognitive or a motor disorder (Heilman et al, 2008). Luria (1965) described 2 subtypes: “efferent perseveration” and “inertia of a previously recorded programme of action.” Efferent perseveration appears as compulsive repetition, while “inertia” is the individual’s being stuck in a pattern of action, unable to switch to another. Sandson and Albert (1984, 1987) divided perseveration into 3 subtypes. In their “stuck in set” subtype, as in Luria’s “inertia,” the person continues a cognitive strategy to solve a problem when a new strategy is needed. In what the authors termed “recurrent perseveration,” the patient repeats an earlier response when given a different stimulus. “Continuous” perseveration” is similar to Luria’s “efferent” subtype in that the patient continues to repeat the same action or behavior without interruption. Typically, perseveration is considered to be induced dysfunction of the frontal lobes (Na et al, 1999; Sandson and Albert, 1984, 1987; Vilkki, 1989) as related to the intentional “when” systems, such as when to start an activity, when not to start, when to continue, and when to stop (Heilman et al, 2008). The network that mediates intention includes the frontal lobes, which project to the www.cogbehavneurol.com |
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striatum; the striatum, projecting to the globus pallidus pars interna or the substantia nigra pars reticulata, which then project to the thalamic nuclei; and finally back to the frontal cortex (Heilman et al, 2008). Perseverative behaviors have been noted in patients with disorders of the basal ganglia networks, including stroke (Nys et al, 2006) and degenerative conditions such as Parkinson disease (Taylor et al, 1986). Animal studies have also found perseverative behavior resulting from temporal-parietal lesions (Denny-Brown and Chambers, 1958). In terms of hemispheric laterality, recurrent perseveration is more often associated with injury to the right than the left hemisphere (Na et al, 1999; Pia et al, 2009). However, Sandson and Albert (1987) found that when patients made drawings on command, some of those with left hemisphere damage and aphasia demonstrated recurrent perseveration. These researchers also reported that continuous perseveration was more often associated with right than with left hemisphere lesions. Because previous studies did not precisely document whether the investigators used only 1 or both of the patients’ hands to test tasks of perseveration, it is difficult to determine whether the disorder was unilateral or bilateral. Still, a few reports have commented specifically on testing that used both of the participants’ hands and found deficits in their performance, indicating bilateral perseverative errors (Kimura, 1977; Ruchinskas and Giuliano, 2003). Fung et al (1997) described patients with clonic perseveration after thalamic or basal ganglia strokes, and noted that the perseverative movements were bilateral, though usually worse on 1 side than the other. Unilateral perseveration has been reported in association with unilateral neglect, although most of the patients were tested only with their dominant hand (Na et al, 1999; Pia et al, 2009; Ronchi et al, 2009; Rusconi et al, 2002). Many of these patients had recurrent or continuous perseveration (Guerrero et al, 2010; Kim et al, 2009). We found only 1 case report (Shahani et al, 1970) in which unilateral perseveration was observed in a patient who also had a strong ipsilateral grasp reflex secondary to a left hemisphere stroke induced by a pericallosal artery occlusion. In our clinic, we studied a patient with probable PSP or CBS who had a profound and disabling continuous perseverative disorder of his right hand. Here we describe this patient and his abnormal perseverative behaviors, and discuss some possible mechanisms of his disorder.
handwriting had become more “jumbled” over time, to the point of illegibility. His personality had changed. He became less interested in initiating activities that he had formerly enjoyed. He became less able to solve problems. When doing chores around the house, he became compulsive, wanting to clean things very thoroughly, but not always doing an effective job. The patient was seen by his local neurologist, who suspected PSP and sent him to our clinic for further evaluation. We evaluated the patient’s cognitive and motor abilities (Table 1). We will discuss his results throughout the case history. On the Mini-Mental State Examination (Folstein et al, 1975), he scored 26 out of 30 points. He lost 1 point each for not knowing the day of the month and for missing 1 iteration of the serial 7’s. He lost the other 2 points because he was unable to write a sentence and copy the design. These latter 2 deficits were not linguisticcognitive, but rather were secondary to his impaired control of motor output. When using his right hand to write the sentence for the Mini-Mental State Examination, he added extra lines within letters and he drew tight squiggles that looked as though he was crossing something out (Figure 1). When he wrote individual letters in response to dictation, his writing with his right hand showed the same extra lines and squiggles (Figure 2A). By contrast, when he wrote
CASE REPORT A 68-year-old right-handed college-educated man had a 2-year history of problems with walking. His family said that overall he had been much slower than usual in both walking and talking. He often lost his balance while walking, usually falling backwards; several weeks before we evaluated him, he had fallen and broken his hip. His
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TABLE 1. This Patient’s Motor and Cognitive Assessment Test
Result
Mini-Mental State Examination1 Fist-edge-palm3 Crossed response inhibition3 Go/No Go3 3
Hand alternation Ideomotor apraxia4
Limb-kinetic apraxia4
Boston Naming Test short form6 Digit span4 Letter fluency4 Category fluency4
26/30; corrected for age and education level: 25/30.2 Preserved orientation to place, naming, repetition, reading, and following commands Impaired bilaterally: unable to achieve after 5 attempts. Perseveration noted in right hand only Normal: 8 of 10 trials correct Impaired bilaterally: 7 of 10 trials incorrect. Perseveration noted in right hand only Normal Impaired bilateral ability to pantomime how to use scissors and whisk eggs. Intact ability to pantomime the use of a hammer and a screwdriver Impaired bilaterally. Time to complete 30 rotations of a nickel using thumb, middle, and forefinger of left hand = 47.8 seconds, right hand = 43.7 seconds. This is equivalent to 31.86 seconds for 20 rotations with the left hand (normal = 14.5 seconds) and 29.1 seconds for the right hand (normal = 13.2 seconds)5 Normal: 14 of 15 correct Normal: 6 digits forward, 3 backward Impaired letter fluency: F/A/S: 4/4/7 Impaired category fluency with 6 animals: 6
1, Folstein et al, 1975. 2, Mungas et al, 1996. 3, Luria, 1966. 4, Doty et al, 1990. 5, Mendoza et al, 2009. 6, Kaplan et al, 1983.
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FIGURE 1. As part of the Mini-Mental State Examination (Folstein et al, 1975), the patient writes a sentence with his right hand. He perseverates, repeating lines within letters and spontaneously writing squiggles.
letters with his left (nondominant) hand, he did not add extra lines (Figure 2B). He showed the same pattern of perseveration when he performed Luria’s alternating graphical sequence test, the “rampart” design drawing test (Luria, 1966). The examiner drew 2 rampart designs and asked the patient to copy the design beneath, with his left hand (Figure 3A)
FIGURE 2. The patient writes individual letters in response to dictation. Panel A: When he writes with his right hand, he shows continuous perseveration. He also has “stuck in set” perseveration: Each character, while illegible, looks similar to the character above it. Panel B: When he writes with his left hand, his letters are individually recognizable and have few extra lines. r
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and his right hand (Figure 3B). Unlike his clean left hand drawing, his right hand drawing again has extra lines and squiggles. The pattern of right-hand perseveration continued in his drawings of the interlocking pentagons given in the Mini-Mental State Examination (Figure 4A). With his right hand, he drew extra lines over the sides of the pentagons (Figure 4B). The drawing that he made with his left hand is much cleaner (Figure 4C). When we assessed the patient for frontal lobe dysfunction (Table 1), we asked him to perform some of the other Luria tasks (Luria, 1966). As with his writing and drawing, he showed severe continuous perseveration of his right hand. For example, we noted the same error when having him perform the “fist-edge-palm” hand sequencing task. In this test, the seated examiner asks the patient to watch her make a sequence of movements and then to perform the same movements. Here is the sequence: With 1 hand, the examiner makes a fist and puts it on her lap. Then she lifts her fist from her lap, opens her hand, and puts the ulnar portion of her open hand on her lap. Then she again lifts her hand, rotates her arm, and puts the palm of her hand on her lap. The examiner usually repeats the sequence of movements 3 times. Then she asks the patient to perform the same sequence with 1 hand and then with the other hand. All 5 times that our patient tried the task with his right hand, he made the first fist-to-lap movement but perseverated on it and never progressed to any of the other movements (Table 1). He did not perseverate when he tried the task with his left hand. We gave the patient a frontal-motor test for echopraxia in which we asked him to tap his hand twice after the examiner had tapped once, and to tap once after the examiner had tapped twice. When he performed the task using his right hand, he would keep tapping his right hand for several seconds, but when he used his left hand, he performed the task without error. When we asked the patient to switch tasks from drawing the interlocking pentagons with his right hand to drawing the Luria ramparts with his right hand, he did not have recurrent perseveration. We gave the patient the crossed response inhibition test (Table 1) (Luria, 1966). In this test, the examiner asks seated patients to close their eyes and put both of their www.cogbehavneurol.com |
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FIGURE 3. For Luria’s (1966) alternating graphical sequence test, the “ramparts” design, the patient is asked to copy a design beneath the example that the examiner has drawn on the page. Panel A: Drawing with his left hand, the patient draws the design cleanly. Panel B: Drawing with his right hand, the patient perseverates, with extra lines and squiggles.
palms on their lap. The examiner explains that she will touch the back of 1 of the patients’ hands, and when she does so, the patients should raise their other hand. This is the “crossed response.” If patients raise the hand touched rather than the opposite hand, it is considered an error. Our patient performed normally on the crossed response task.
We gave him the hand alternation test (Luria, 1966). In this test, patients put both hands on their lap. They watch the examiner perform the task and then try it themselves. They are asked to flex the fingers of 1 hand and make a fist; they are to hold the other hand open with the fingers extended. Then they are asked to switch these
FIGURE 4. In the Mini-Mental State Examination (Folstein et al, 1975), the patient copies interlocking pentagons from the original (Panel A). He perseverates when drawing with his right hand (Panel B), but not his left hand (Panel C).
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postures repeatedly between their hands. Our patient also performed normally on this hand alternation test. On the Hopkins Verbal Learning Test (Brandt, 1991) and other recall tasks, he often repeated the words spoken by the examiner (echolalia). He also demonstrated bilateral ideomotor and limb-kinetic apraxia of his hands (Table 1). He showed neither apraxia of speech nor a nonfluent aphasia. He scored normally on the Hopkins Verbal Learning Test (with a retention of 85%), the Boston Naming Test (Kaplan et al, 1983), and digit span (Table 1). His letter and category fluency scores showed impairment (Table 1). He did not display any left-right confusion. As for the rest of his neurologic examination, cranial nerve testing showed that his pupils were equally round and reactive to light. He had full visual fields, and no evidence of visual inattention or extinction. Testing of his extraocular movements revealed that both eyes had a limitation of vertical (up and down) saccades as well as pursuit. He had a positive oculocephalic reflex, with passive movement of the head in all directions. Facial sensation was intact. He had a mask-like face with an abnormally low spontaneous blink rate. His speech was hypophonic. He tended to repeat words even during conversation (echolalia). The motor examination revealed increased tone (plastic rigidity) in his neck, but normal tone and strength in all his limbs. Because of his recent hip fracture, we tested his right leg cautiously. He had bradykinesia and hypokinesia in both of his arms and hands. He also had tactile mitgehen of both hands: The examiner told him to put his hands on his lap and keep his arms and hands relaxed. Then the examiner touched him lightly on his fingertips. As she tried to move her hand away, the patient moved his hand to keep his finger in contact with her finger (Fitzgerald et al, 2007). We tested the patient for an “avoidance response.” He held his hand supine and fully relaxed, with his fingers hanging down. The examiner rubbed her forefinger against the patient’s palm and then out to the tips of his fingers. During this stimulation, the patient extended his fingers. This was an avoidance response, which is abnormal and evidence of parietal dysfunction (DennyBrown and Chambers, 1958). His avoidance response was mild, but greater in his left hand than his right. His reflexes were symmetric and he had bilateral palmar grasp. His plantar response was extensor in both feet. The sensory examination was normal, without evidence of inattention or extinction. We could not evaluate the patient’s gait because of his hip fracture. Magnetic resonance imaging (MRI) of the patient’s brain (Figure 5) disclosed mesencephalic atrophy consistent with the “hummingbird sign,” which is seen in many patients with PSP. The characteristic midsagittal MRI image of midbrain atrophy without pontine atrophy looks like a hummingbird (Graber and Staudinger, 2009). The patient’s scan did not show lateralized cortical atrophy or any abnormality in the corpus callosum. r
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FIGURE 5. Magnetic resonance imaging scan of the patient’s brain. This midsagittal fluid attenuated inversion recovery section shows the classic midbrain atrophy (“hummingbird sign”) of progressive supranuclear palsy.
A positron emission tomogram obtained by the patient’s original consulting neurologist showed subtle bilateral frontal and temporal reductions of activity, without indication of lateralized changes. On a follow-up examination 12 months after admission, the patient’s symptoms had not changed markedly from his original presentation.
DISCUSSION As originally described by Steele et al (1964), PSP has as its classic hallmark a supranuclear ophthalmoplegia, primarily affecting vertical gaze. Patients also have pseudobulbar palsy, axial dystonias, and evidence of frontal-subcortical cognitive dysfunction (Albert et al, 1974), with characteristic midbrain atrophy seen on imaging (Jankovic, 2012). As noted by Kouri et al (2011), patients with CBS can present with several different syndromes. Parkinson disease and some of the parkinsonian spectrum disorders, such as CBS, commonly affect 1 side of the body more than the other. In contrast, PSP of the Richardson type (“PSP-R”) (Williams et al, 2005) typically affects both sides of the body almost equally. Our patient’s clinical history, cognitive testing, and elements of his neurologic examination were consistent with a diagnosis of PSP, and his brain MRI revealed the classic mesencephalic atrophy of PSP. Patients with CBS can also manifest parkinsonian signs and dementia, in contrast to patients with the Richardson type of PSP (Williams et al, 2005); however, many patients with CBS www.cogbehavneurol.com |
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have asymmetric signs, as did our patient. Patients with CBS can have an asymmetric alien limb; while our patient did not reveal a classic CBS alien limb, he had an asymmetric avoidance response that may have been the first sign of alien limb. Many patients with CBS have either an asymmetric ideomotor or limb-kinetic apraxia; while our patient did have both of these forms of apraxia, he had no limb asymmetry. While the typical syndromes of PSP and CBS are distinct, many patients, like ours, have an atypical PSP-CBS syndrome with overlapping clinical features. Unlike previously reported patients with PSP or CBS, our patient demonstrated continuous unilateral hand motor perseveration. However, other than his perseveration when using his right hand, he did not have asymmetric motor signs. It is possible that his asymmetric perseveration was a sign of further dysfunction of his right hemibody. While, as mentioned, CBS is often characterized by asymmetric rigidity, asymmetric apraxia, cortical sensory deficits, and myoclonus, some patients do not develop these features, but instead have features consistent with the Richardson form of PSP. They present with postural instability, falling, and a vertical supranuclear gaze palsy, as did our patient. Unlike patients with a second form of PSP, called the parkinsonian form, our patient did not have a tremor or asymmetric parkinsonian signs. The pathophysiology of our patient’s unilateral perseveration is not known, but there are several possibilities. Because his perseveration was primarily of his right hand, it is likely that the locus of the dysfunction was within his left hemisphere. Ronchi et al (2012) studied the perseveration errors observed during a cancellation task in patients with neglect, and found that these errors were most often associated with lesions of the insula. Whitwell and colleagues (2010) reported that patients with CBS had atrophy of the insula. Although we did not see any asymmetric atrophy of our patient’s insula, it is possible that atrophy of this region contributed to his unilateral motor perseveration. Stoffers et al (2001) suggested that perseveration may be an early indicator of Parkinson disease and related to basal ganglia dysfunction. Thus, another possible cause of our patient’s unilateral continuous perseveration may be related to basal ganglia dysfunction. Right hemisphere lesions can be associated with continuous perseveration of both the left and right hands. Nys and coworkers (2006) reported that damage to the caudate nucleus was an important correlate of perseveration, independent of whether patients showed hemineglect. Pia and colleagues (2009) concluded that perseverative errors were associated with right basal ganglia lesions. Studies of patients with CBS have shown that they may have atrophy of the head of the caudate (Su¨dmeyer et al, 2012). Therefore, it is possible that asymmetric degeneration of the head of the caudate, which is strongly connected with the frontal lobes, may have played an important role in our patient’s unilateral perseverative behavior. Kleinman and colleagues (2013) also studied motor perseveration in patients with right hemispheric strokes,
including patients who did not show neglect. The authors found that the lesion most commonly associated with motor perseveration was injury to the right dorsolateral frontal lobe. Unlike Nys et al (2006), Kleinman et al (2013) did not find that caudate injury was related to perseveration. However, the dorsolateral frontal lobes are known to have strong connections with the caudate (Leh et al, 2007). Kouri and colleagues (2011) reported that atrophy of the anterior corpus callosum is a potential marker to differentiate CBS from the Richardson form of PSP. As mentioned, the continuous motor perseveration of our patient’s right hand and his propensity to repeat words suggest that the cause was his left hemisphere dysfunction. Although we do not know the locus or loci of the responsible left hemisphere dysfunction, in light of Kouri et al’s (2011) report it is possible that the mechanism of his perseveration was a partial callosal disconnection. Our patient did not show evidence of callosal disconnection, such as hemi-alexia or extinction to bilateral simultaneous stimulation. These signs, however, are often associated with posterior callosal dysfunction. One of the best signs of injury to the anterior corpus callosum is ideomotor apraxia of the left hand. Our patient did have ideomotor apraxia of his left hand, but he also had apraxia of his right hand. Thus, we cannot know if his left hand apraxia was related to a callosal disconnection, left hemispheric dysfunction, or even bilateral hemispheric dysfunction. Although our patient’s MRI did not show overt evidence of a corpus callosum abnormality, his clinical changes could potentially precede any appreciable radiographic evidence. We also note that he underwent a routine protocol MRI as part of a dementia work-up. More detailed imaging, such as with tractography, might have highlighted subtler differences than were visualized on his scan. Further laboratory tests such as electroencephalography and single-photon emission computed tomography might also have helped to determine if he had any other asymmetric patterns of brain activity. As mentioned, the 1 case report that we unearthed commenting on unilateral perseveration and grasp reflex (Shahani et al, 1970) reported the disorders to be secondary to a pericallosal artery occlusion, further implicating callosal damage. Several studies have shown that right hemisphere dysfunction can be associated with bilateral perseveration (Kleinman et al, 2013; Pia et al, 2009; Sandson and Albert, 1987). The finding that patients with right lateral frontal lobe or caudate injury have bilateral motor perseveration suggests that normally the network formed by the right frontal lobe and caudate plays a critical role in determining when an action should be terminated. Because the right hand is controlled by the left premotor and motor cortex and the right frontal lobe is important in terminating activity, the right frontal lobe must communicate with the left hemisphere’s motor areas, and this
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communication most likely occurs through the corpus callosum. Thus, if the right hemisphere is intact but the corpus callosum is injured, then the left hand will not exhibit motor perseveration. But the right hand, being disconnected from the right frontal lobe, may exhibit motor perseveration. Sine et al (1984) reported a patient who had a “full callosal syndrome,” with perseveration on 1 side of the body, specifically when doing spatial tasks with the right hand and doing symbolic tasks with the left hand. For example, when copying a flower with the right hand, the patient would perseverate and draw the petals numerous times. In contrast, the left hand appeared to be “stuck in set”: After the patient drew a clock face, he was asked to write his name, but he again began to write the numbers of a clock. Sweet (1941) reported a patient who had an aneurysm of the left anterior cerebral artery that led to softening and destruction of parts of the corpus callosum. Although not discussed by Sweet, when we reviewed his report and his patient’s writing sample, we saw that she perseverated when she wrote with her right hand. For example, when she tried to write “Chicago,” she wrote, “Chicacaqo,” perseverating on the “ca.” This observation suggests that corpus callosum injury, even with sparing of the frontal lobes, basal ganglia, and insula, can lead to perseveration. Future studies of patients with CBS or the parkinsonian or Richardson form of PSP, assessing each hand independently with tests like Luria’s fist-edge-palm, may let us learn if any of these diseases are associated with asymmetric hand perseveration. It is also possible that our patient had a form of a parkinsonian spectrum disorder that has not yet been described and that might be called perseverative progressive supranuclear palsy. Further studies of the neuropathology of our patient or other patients with the same disorder may also help us understand its relationship to other parkinsonian spectrum disorders.
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