Neuro-Oncology
Anti-LGI1 encephalitis
Oct. 03, 2024
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Alien hand syndrome …
- Updated 02.13.2024
- Released 11.12.1997
- Expires For CME 02.13.2027
Alien hand syndrome
Introduction
Overview
Alien hand syndrome describes any of several neurologic disorders that share the appearance of seemingly purposeful movement by one hand that is dissociated from the conscious intent of the patient, giving the impression that the limb is acting on its own. Less often, one leg behaves in this manner, and, thus, the alternate and more inclusive term “alien limb” is widely used in the scientific literature (42). The author reviews the different manifestations and causes of this complex disorder, as well as variants of this phenomenon. The disorder has been recognized in diverse cerebral illnesses, including stroke, corticobasal syndrome, and multiple sclerosis, as well as following corpus callosotomy for refractory epilepsy. Although primarily an adult disorder, alien hand may also occur in children. Therapies for this disorder have not been well developed. Several pharmacologic approaches have been published but without replication. Verbal commands from another individual or generated by the patient himself or herself can control the phenomenon, but it is not clear whether this approach can confer lasting benefit. Some evidence indicates that compulsive grasping may be modulated by the degree of danger involved, reflecting some amount of “top-down” control.
Key points
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• Alien hand is a rarely diagnosed disorder following brain illness that involves complex, apparently goal-directed movement of one hand for which the patient lacks conscious intention. | |
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• The disorder can be mistaken for psychiatric illness and can greatly trouble patients. | |
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• Consistently successful treatments have not been developed. | |
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• The clinician’s recognition of the characteristic presentation of the disorder could help to reduce the patient’s anxiety. |
Historical note and terminology
Alien hand syndrome is not consistently or precisely defined. It describes seemingly purposeful activity by one hand that is not voluntarily mediated, though often the “purpose” is not clear. The patient is unable to explain the source of such movement and may consider the limb to move as if it had a mind of its own. It has been proposed that alien hand should be strictly defined as involuntary movements of the limb, whether appearing purposeful or not, and should be associated with a sense of loss of ownership of the action (66). The key term is the “sense” of lack of ownership, without the patient expressly denying limb ownership, which can occur in other disorders.
Essentially, three kinds of behavior are covered by this term. The first two were described in a seminal paper (50). The first consists of repetitive involuntary grasping. Beginning in 1900, Liepmann drew attention to the unilateral, disinhibited grasp reflex to tactile stimulation after cerebral injury (96), although this phenomenon had been described by Kaiser as early as 1897 (128). Liepmann's detailed descriptions of disinhibited grasp reflex and unilateral apraxia quickly inspired other German investigators to contribute their own observations of acquired complex movement disorders. Among them, Van Vleuten reported a patient with a left hemisphere brain tumor that had invaded the corpus callosum (141). The patient repeatedly grasped and put down an object with his right hand, apparently unintentionally. Goldstein first connoted the "alien" quality of unilateral repetitive grasping, the impression that an alternate entity is responsible for the behavior (60). His patient complained, "There must be an evil spirit in the hand!" In succeeding years, such behavior or other phenomena that suggested disinhibited, complex, and seemingly autonomous movements became formally labeled by terms that included, "pseudospontaneous movements" (146), Nachgreifen (pursuit grasping) (128), "magnetic apraxia" (40), “manual grasping behavior” (93), the "groping-grasping reaction" (100), “visual groping” (148), and tactile mitgehen (manual pursuit movement) (52).
The second behavior covered by the term “alien hand syndrome” involves usually unilateral, more complex goal-directed limb movements that are contrary to the individual's conscious (verbalized) intention and not accounted for by repetitious grasping or unilateral apraxia. Van Vleuten's patient appears to have been the earliest reported instance of this condition (141). In this case, the patient's left hand was not only apraxic but also performed markedly incorrect actions, such as touching his right hand instead of his nose, despite his understanding the command, and failing to move when commanded. Self-oppositional behavior, wherein one limb counteracts the declared or consciously intended action of the other limb, was often noted after complete or partial surgical division of the corpus callosum (callosotomy) to treat refractory epilepsy (142; 130). Akelaitis termed such behavior "diagonistic dyspraxia" (01). Brion and Jedynak coined the French term la main étrangère (the foreign hand) to describe diverse behaviors in patients with callosal tumors that included either the failure to recognize self-ownership of the limb or the absence of self-control over the limb's goal-directed actions (21). In either case, the disturbance conveyed the impression of an alternative, silent, simultaneously coexisting "self" governing one side of the body, contrary to the bodily awareness and control that could be accessed introspectively. Of these two disturbances, the former is better termed “somatoparaphrenia” (77) or “asomatognosia” (138) and is usually associated with hemianesthesia.
Self-oppositional activity was also termed "intermanual conflict" by Bogen (17); he introduced the English term "alien hand," a translation of Brion and Jedynak's la main étrangère. Bogen intended "alien hand" to indicate a milder state of intermanual conflict among patients with surgical callosal lesions, wherein the individual finds one hand strange or uncooperative. Goldberg and colleagues applied this term to stroke patients with intermanual conflict, one of whom also had disinhibited groping (59). From this point onward, "alien hand" came to describe these two different motor disorders: (1) disinhibited groping and (2) self-opposition. However, investigators have not exercised restraint when reporting involuntary movements or postures in their patients. Thus, "alien hand" has been extended to include non-goal-directed, involuntary tonic posturing (22; 74; 127), even though the patient may not indicate any sort of alien quality (08). An “alien leg” counterpart to such activity, which appeared as either involuntary complex movements of the toes of one foot or freezing or bending of the leg, has also been reported (73). Nonspecific epileptic movements that are associated with feelings of loss of ownership for the limb have also been reported as “alien limb” (16). These unfortunate corruptions of the term complicate its usefulness.
Marchetti and Della Sala proposed "anarchic hand" as an alternative term for involuntary and seemingly purposeful activity but without the patient considering the limb to be foreign (101). This term has become widely used, though it is used less often than “alien hand.” “Anarchic hand” has also been applied to diverse behaviors, which adds to the confusion.
The third behavior describes intermittent unintended levitation, posturing, or lack of voluntary movement of one limb, with or without more complex phenomena or indication that the patient regards the behavior as unintended. This may follow stroke but is most often described in corticobasal syndrome (62; 30). Phenomena consistent with this form of alien hand have been reported since corticobasal syndrome was identified as a distinct disorder (120).
Despite the substantial diversity among these disorders, "alien hand" has become the preferred term for these disparate disturbances of motor self-control. This is regrettable because different pathophysiological mechanisms probably underlie the diverse behaviors in alien hand. In view of the wide variety of acquired disorders of voluntary movement, what constitutes or does not constitute alien hand seems to have been arbitrarily decided.
Clinical manifestations
Presentation and course
Alien hand syndrome is an intermittent involuntary movement disorder. The patient must be aware of the disturbance (at least some of the time) to indicate the lack of voluntary initiation of the abnormal activity, although at its onset, the behavior may not be noticed by the patient until pointed out by a clinician (07; 134). The movement must appear to be directed to a particular object or to conduct a specific task. Nonspecific involuntary muscular contractions (eg, clonus, tremor) are, therefore, excluded. The patient's comments should convey the impression that the involved limb behaves as if it were under the purposeful command of an individual other than the patient. Such comments may reflect depersonalization so that the errant hand assumes a distinctly different "personality." The patient may complain of the hand, "It doesn't want to stop," or "I can't make it listen to me." Patients usually recognize that they have an illness that induces the disturbance, rather than believe that a supernatural force possesses them.
Three kinds of alien hand are generally recognized. In the first, the “frontal” variant, the patient has disinhibited groping, an unintended reaching for seen objects that fall within arm's reach (visual grasp) or that have been removed from contact with the hand. Once seized, the patient has difficulty letting go of the object and may repeatedly clutch at the object. Paradoxically, at times the patient may have difficulty willing the limb to move. Patients sometimes describe an urge to move in this variant (28).
The grasp reflex to tactile stimulation is usually present, although some exceptions have been reported (102), and tone is increased in the limb. A tightening of the grip occurs the more that the patient attempts to release the object. With concentrated effort the patient can release the object; however, with distraction the phenomenon may be reinstated (144). The right hand is more often involved than the left hand, reflecting the greater association with left hemisphere injury (48).
In the second kind of alien hand, the “callosal” variant, the patient's hand counteracts voluntary actions performed by the other, "good," hand. For example, the patient may pull off a sock immediately after it has been put on, close a drawer that has just been opened, turn a car's steering wheel in the opposite direction of that of the good hand, etc. (10). In general, such self-oppositional behavior does not appear unprompted, but rather follows the voluntary action by the unaffected limb (20). This is also termed “intermanual conflict.” Sometimes the alien behavior seems not to counteract the unaffected limb's activity but instead acts without a clear functional relationship to the action of the unaffected limb (137). Occasionally, however, the involuntary movement occurs without being preceded by activity in the unaffected limb (61). Video demonstrations of callosal alien hand are available in online journal supplements (103; 105). Another phenomenon associated with callosal alien hand has been termed agonistic dyspraxia, in which one hand does not respond to command and the contralateral hand compulsively performs the requested act (87). Following callosal injury, either hand may behave in this manner.
Callosal alien hand nearly always affects the left hand (48), but at least one instance has been reported where the dominant right hand apparently acted in this manner (57). Involuntary oppositional behavior of one leg may also appear, often ipsilateral to the alien hand (27).
Less commonly, a third kind of alien hand has been reported, consisting of ataxic limb movements associated with anesthesia or hypesthesia of the limb (22). This has been termed the “sensory (or posterior)” alien hand variant (06). Complex limb movements (such as grabbing at the steering wheel of a car) have also been described with this disorder (79). The limb anesthesia prevents proprioceptive monitoring of limb position, and this in turn may impair motor control of the limb as well as hinder recognizing the limb as part of one's own body. In one instance, spontaneous left arm levitation occurred in a patient following a stroke, which occurred so rapidly that the patient suffered left eye injury from his striking himself while he dressed himself (126). Because he was also already visually impaired, he could not prevent this injury. He requested the limb to be tied down.
A similar disorder has been observed following acute parietal injury but without evident tactile impairment. It consists of involuntary limb posturing and exploratory movements, unilateral neglect, and denial of the disorder (124). This disorder may arise due to loss of parietal input to motor cortex, causing impaired voluntary movement regulation by motor cortex that may be exacerbated by inattention to the limb. This third variant may not so convincingly be regarded as alien hand as the other two because the movements lack a clearly purposeful character.
Sometimes more than one kind of alien hand appear in the same individual (125), including one kind of alien hand in one limb and the other kind of alien hand in the other limb (24; 88). Alternatively, the same kind of alien hand (either self-oppositional behavior or involuntary grasping) may appear in both upper extremities (98).
A few case reports have indicated self-contradictory communicative behavior (gestures or speech) in patients following callosal damage (01; 86; 110). The report by Nishikawa and colleagues furthermore indicates instances where, in effect, inner speech or other forms of intrapersonal desires were in self-conflict. These studies indicate that self-oppositional behavior is not limited to limb motor disturbance.
Prognosis and complications
Alien hand generally recovers within a year of focal acute brain injury (29). However, exceptions exist. One case of alien hand that occurred following cerebral gunshot wound to the callosum persisted for 12 years until the patient died of nonneurologic disease (09). Other reports have described intermanual conflict for as long as 3 to 4 years after cerebral injury (51; 24). Presentations of alien hand may also be delayed following acute brain illness, as in an instance of callosal alien hand that appeared 3 months after an episode of epilepsia partialis continua (81) or after post-stroke unilateral spatial neglect at 2 months’ follow-up (145). The appearance of alien hand was associated with concurrent MRI evidence of progressive cerebral atrophy since the onset of the illness. In contrast, it may be possible that acute structural neuroplastic reorganization may ameliorate alien hand. A case report of the callosal alien hand syndrome following callosal hemorrhage observed in diffusion tensor imaging at 4 weeks post-onset the anomalous extension of posterior callosal fibers toward frontal areas, coinciding with recovery from the disturbance (75).
In contrast to acute focal injury, alien hand associated with progressive degenerative cerebral disorder may persist indefinitely, or cerebral degeneration may advance so far that it interferes with limb mobilization (45).
Alien hand generally does not pose risks. However, potentially self-injurious behaviors by the hand have been reported, such as self-directed slapping, choking, and scratching (116; 23), but these phenomena have not been noted to cause serious injury. Unwanted violent actions directed toward the examiner were reported in one case of frontal alien hand (123). The alien hand's grasping a hot utensil (58; 61) or a sharp or self-powered tool, particularly an automobile steering wheel (61; 91), obviously risks great injury to the patient and must be avoided. In an experimental study of frontal alien hand, the degree of danger from objects presented within grasping distance (eg, a lit candle, broken glass) appeared to limit the patient’s compulsion to reach (105). Compulsive grasping has also been associated with self-directed skin abrasion (58). In another case, a patient with intermanual conflict lost control of using a walker due to the attempt by the alien left hand to interfere with using the dependable right hand (44).
Clinical vignette
A 71-year-old right-handed woman developed acute left hemiparesis and visual hallucinations. She also complained that her left hand uncontrollably scratched her and pulled at her hair. Past medical history was notable for chronic hypertension and triple coronary artery bypass graft 6 years earlier. Two weeks before the illness, she had felt diffusely weak; another hospital had attributed this weakness to metoprolol toxicity. When her complaints did not subside after two days off medication, her husband brought her to the emergency room. Evaluation disclosed full orientation, left lower facial weakness, right gaze bias, left hemibody hypesthesia, and extensor posturing of the left limbs, with the left hand constantly clenched. Cranial CT scan indicated acute right parietal cortical infarct and extensive bilateral subcortical white matter ischemic changes.
She was hospitalized and experienced no further hallucinations. She initially had constructional apraxia and impaired temporal orientation and abstraction. Her Mini-Mental State Exam score (53) improved from 18 to 23 (maximum score is 30) during her stay. Cerebral MRI scan 6 days after admission confirmed the subacute right parietal infarct and diffuse bilateral subcortical ischemic changes.
Carotid ultrasound examination indicated no surgically significant disease, so she was transferred to a rehabilitation hospital 9 days after admission. On the patient's arrival, the physician wrote in her chart, "The patient refused to attempt to do anything with that hand because 'it will hit me in the face.' The patient talks of her hand as if it were a separate entity."
Self-care ability improved during the 1-month rehabilitation stay but was nonetheless disrupted by the left hand's involuntary grasping and failing to release objects despite being commanded to do so. However, "the patient could actively request the hand verbally to let go of objects, and this sometimes resulted in improved control. The patient also demonstrated an increasing ability to spontaneously use the left upper extremity when not having conscious effort directed towards that function."
Informal follow-up evaluation in the patient's home about 10 weeks after illness onset disclosed consistent involuntary left-hand grasp to gentle tactile stimulation and a tendency for the left hand to repeatedly touch her face with her eyes closed, despite being instructed to keep the upper extremities extended. She also showed bilateral tactile anomia, agraphesthesia, and impaired joint position sense. Light touch sensitivity was symmetrically present in the upper extremities. The left arm showed tonic posturing; it would either be maintained at rest with the elbow flexed or was pronated when the arms were outstretched. The right arm moved normally. No autonomous groping was observed. Further information on the patient's outpatient course is not available; she died within the year.
Discussion. Alien hand was suggested by the patient's involuntary self-grabbing and her referring to her hand in depersonalized terms. The etiology was somewhat unusual because the apparently acute radiologic finding was a contralateral parietal infarct. However, the neuroimaging studies suggested chronic paracallosal ischemic leukoencephalopathy. Possibly, the combination of left hypesthesia induced by the acute parietal infarct with chronic medial frontal ischemia sufficed to induce alien hand. Thus, the patient showed poor awareness for the spatial location of the arm, and this in turn may have impaired somatosensory feedback that would otherwise have prevented her left upper extremity from groping at her face due to medial frontal injury. The medial ischemic damage alone may have been insufficient to cause alien hand. Thus, the patient may have had the sensory alien hand variant (06). Unfortunately, other case reports with similar clinical and radiologic presentations have not appeared for comparison.
Biological basis
Anatomic localization
Various kinds of alien hand are associated with different locations of structural damage. The disorder characterized by groping is usually associated with damage to the contralateral medial frontal cortex, near or involving the supplementary motor area (59), although the frontal variant has also been seen following parietal injury (05; 62). The lesion is contralateral to the affected hand and has been reported to be three times more likely to be in the left hemisphere than in the right (48). The largest review of cases of alien hand at a single institution (n = 150) in contrast reported right hemisphere predominance (62). However, this series appears to have included patients with nonspecific wandering of the hand without the semblance of goal-directed behavior, thus, making it unclear whether alien hand that has goal-directed activity primarily results from right hemisphere injury.
Self-oppositional behavior is generally associated with damage to the body of the corpus callosum, particularly the ventral portion of the posterior third of the callosum (137), although one instance was apparently caused by cerebral infarction of the right parietal lobe (82). In a small series of patients with corpus callosum infarction, alien hand syndrome occurred in only 3% of such patients, which were associated only with extensive damage to the callosum (94). Oppositional hand behavior following a ruptured cerebral aneurysm and consequential subarachnoid hemorrhage follow from involvement of the anterior communicating artery more often than the pericallosal artery (88). Often, however, these two variants of alien hand are found together, and structural damage involves both the medial frontal cortex and the corpus callosum.
A third, less commonly reported location for injury associated with alien hand is in the posterior cerebral cortex or underlying structures (12), or the brainstem (119). Two patients have been reported with ictal alien hand following contralateral parietal injury (91). One patient suddenly felt uncertain about the arm's spatial location, whereas the other patient suddenly sensed that the arm did not belong to her. Another report of ictal alien hand with similar features followed from frontotemporal lobe lesion (49). Three patients have been reported with acute parietal injury, without clinically evident somatosensory loss, but with hemibody neglect and denial of their autonomous limb movements (71). A case report of recurrent, episodic posterior alien hand was associated with two relapsing episodes in a patient with multiple sclerosis (85).
Alien hand also has been frequently associated with corticobasal syndrome. In such patients, the achromasic, ballooned neurons and neuronal loss occur primarily in the frontal and parietal lobes, thalamus, and substantia nigra (55; 122).
Pathophysiology
The variants of alien hand differ not only in character but also in localization. Disinhibited groping that occurs consistently with tactile or visual stimulation is primarily related to medial frontal lobe injury, whereas self-oppositional behavior occurs more variably in the patient and is primarily associated with midcallosal damage (137). Alien hand associated with impaired somatosensory input usually follows posterior cerebral injury. Therefore, different pathophysiologic mechanisms are likely responsible. The feeling of alienation likely results from the disinhibited, excessively reactive responses that appear to be purposeful with intact error monitoring (14).
Frontal alien hand may reflect disinhibited parietal function. Denny-Brown demonstrated during his experimental work in monkeys and observations on humans with localized lesions that the frontal and parietal lobes seem to have opposing functions (39). Parietal injury results in inattention and lack of orientation toward contralateral space, or unilateral spatial neglect syndrome. In rare cases of parietal injury, the patient may extend rather than flex the fingers to the approach of a stimulus; Denny-Brown termed this “avoidant reaction.” In contrast, frontal injury, particularly in the supplementary motor area of the medial frontal lobe, results in contralateral disinhibited grasp reflex and groping. From these observations, Denny-Brown concluded that the individual's relationship to surrounding space involves a balance between approach and avoidance. The frontal lobes are specialized for avoidance, whereas the parietal lobes are specialized for exploration. Frontal lesion may result in disinhibited exploration (groping), whereas parietal lesion may result in excessive environmental withdrawal, avoidance, or unawareness. However, in a case of combined acute parietal, temporal, and occipital right hemispheric infarction, left hand disinhibited grasping appeared to have resulted from extensive intrahemispheric white matter deterioration that extended to the frontal lobe (115). Thus, the disinhibited manual behavior may be accounted for by extensive subcortical damage as shown by diffusion tensor imaging, which was not evident from conventional brain MRI.
Observations in a case study following medial frontal injury indicated that involuntary object grasping depended on the proximity of the objects to the alien hand (57).
Goldberg and Bloom revised Denny-Brown's ideas to suggest that the medial frontal cortex is part of a medial premotor system that anticipates movement and, thus, is vital for monitoring internally generated voluntary control. In contrast, a separate, lateral premotor system primarily reacts to external stimuli. Hence, medial frontal damage interferes with the patient developing a sense of purpose to movement generated by the reactive lateral premotor system under parietal disinhibition, resulting in alienation (58). Environmental stimuli may not only stimulate particular motor patterns but also be used to cue correct performance. Therefore, patients with movement disorders following either medial frontal injury (such as alien hand) or medial frontal hypometabolism (such as parkinsonism) may benefit when they are cued to attend to their motor performance (113).
The frontal alien hand variant may occur in either hand and reflects contralateral medial frontal injury (90). However, the frontal variant more commonly affects the dominant hand (50), perhaps because right (nondominant) hemispheric injury is more likely to produce hypokinesia of the contralateral hand than is left (dominant) hemispheric injury. Such hypokinesia may overshadow alien hand resulting from right hemispheric injury (29).
Physiologic evidence for increased cortical excitability (or decreased cortical inhibition) was demonstrated in patients with alien hand following stroke (118) or corticobasal degeneration (140). An fMRI study of one patient with frontal alien hand variant following focal parietal infarction demonstrated strictly unilateral activity (contralateral to the alien hand) during alien movements but bilateral hemispheric activity during voluntary movements (05). The findings suggest that bilateral hemispheric engagement may be required for voluntary control in such patients.
The callosal alien hand variant occurs preponderantly in the nondominant hand (50; 29). This asymmetry may arise because voluntary, particularly skillful activity is primarily mediated by the left cerebral hemisphere (67), at least among right-handed individuals. The callosal pattern may emerge from the left hemisphere's failure to inhibit the right hemisphere through the corpus callosum (50). Tanaka and colleagues proposed that callosal injury blocks communication between the superior parietal lobules (137). Supporting evidence demonstrated degeneration of the white matter fibers connecting the frontal and parietal areas across the corpus callosum in a case of opposing behavior by the left hand following a callosal hemorrhage, based on diffusion tensor imaging on MRI (13). The desire for a specific movement may occur in both hemispheres simultaneously. Without the communication between the left and the right superior parietal lobules, each hemisphere may independently prepare to act with the contralateral hand, leading to self-conflict. The choice of a hand to move can be experimentally manipulated in healthy individuals by applying single-pulse transcranial magnetic stimulation to the ipsilateral posterior parietal cortex (112). The left hemisphere's lack of influence on the right after callosal injury is variable, for unknown reasons, leading to intermittent alien hand alternating with cooperation between the hands. However, this hypothesis does not explain why the callosal alien hand may reverse the dominant hand's action (such as closing a drawer when the dominant hand has opened it), rather than merely compete to control an object. Such reversal suggests that the right hemisphere may evaluate the right (dominant) hand's action that is not under its control and react by the left hand's reversal of the action because the right hand's action does not match the right hemisphere's intent. This could explain the repeated cycling of alternating and opposing hand control that has been described for some common activities among split-brain patients (01). Lesion to the supplementary motor area may reduce inhibition of reaching, along with disruption of feedforward signals during movement, which prevents a sense of responsibility for the activity (84). Similar behavior was observed following infarction of the medial parieto-occipital and thalamic areas (34). The concurrent loss of proprioception and left hemianopia were considered to contribute to the loss of sense of initiation of limb movement, as well as deficient ability to monitor the limb’s movement itself.
The sensory or posterior alien hand variant, caused by predominantly posterior cerebral injury, may arise from the combination of contralateral hemianesthesia and ataxic limb movements (06). The dense sensory loss of the limb may interfere with the individual's recognition of self-ownership and, hence, the patient may attribute spontaneous limb movements (that occur without proprioceptive feedback and, thus, may be clumsy and dissociated from conscious intent) to the activity of an independent entity. However, posterior alien hand has been observed following combined parietal and corpus callosum infarction affecting the splenium, producing hemianopia but minimal somatosensory deficit (56). Experimental evidence of reduced self-ownership was found in a patient with a combined callosal-posterior variant of alien hand (76). The patient, who watched video displays of his own hand versus a different person’s hand, scored much lower than healthy individuals on a questionnaire on self-ownership.
In a study of patients with corticobasal syndrome, those who were considered to have sensory alien hand (including involuntary levitation of the nondominant arm) were distinguished from patients without alien hand by a reduced amount of regional cerebral blood flow to the right thalamus (38). In a distinguished instance of corticobasal syndrome, the dominant hand uncontrollably levitated during professional piano playing (02). A single photon emission computed tomography (SPECT) study of the patient showed hypometabolism of the contralateral parieto-occipital cortex, whereas diffusion tensor imaging demonstrated extensive structural white matter disruption involving the contralateral frontotemporal region and into the ipsilateral parietal lobe.
Horenstein and colleagues reported three parietal-lesioned patients without alien hand (due to their failure to acknowledge the deficit) who had clinically intact tactile function but involuntary posturing of the contralateral limb and contralateral neglect (71). One of the patients appeared to have exploratory finger movements that compromised self-care. The authors suggested that despite the lack of clinically evident somatosensory dysfunction, the disturbance arose from interference with parietal afferents to ipsilateral primary motor cortex, thus, leading to impaired regulation of voluntary movements, exacerbated by spatial neglect. They termed the disorder "strangelovian hand" after the protagonist in the 1964 Stanley Kubrick movie "Dr. Strangelove," whose crippled right arm showed involuntary self-aggression and fascist salutes. The same sobriquet has been applied by other authors to alien hand (54; 37).
Epidemiology
The epidemiology of alien hand is little investigated, most likely because it is rare and, thus, cannot predictably occur except at the largest medical centers; diagnostic criteria have not been well developed either. Post-stroke alien hand has been reported to occur in one of 1796 patients (0.006%) in a series, but it was not clear how the disorder was diagnosed (69). In hospital series, alien hand has occurred in 3% of patients with corpus callosum infarction (94; 99). In a retrospective survey of alien hand at the Mayo Clinic, the vast majority of cases stemmed from corticobasal syndrome (108/150, or 72%). A comparable incidence was reported at Cambridge, UK (92). Less often were causes ascribed to stroke, Creutzfeldt-Jakob disease, tumor, or other conditions (62; 74; 108). In a case of Parry-Romberg syndrome, alien hand-like phenomena were reported in a 9-year-old patient; however, alienation was not described (136). The youngest patient to complain of alienation was a 15-year-old girl with a callosal hemorrhage (13). The eldest was a 94-year-old woman who had developed the callosal alien hand variant following a right parietotemporal lobe infarct (35).
Differential diagnosis
Confusing conditions
A wide variety of disorders may be associated with involuntary movements that superficially resemble alien hand. The diagnostic features of alien hand alone are broad, including three distinct disorders. Thus, the diagnostic criteria for alien hand seem arbitrary, partly because certain other similar disturbances are not usually included. Essentially, the diagnosis of alien hand should meet the criteria of estrangement from the limb plus observable involuntary activity (45). Nonetheless, familiarity with the differential diagnosis of alien hand not only facilitates diagnosis and treatment but also invites considering the physiologic basis for willed movements.
Although an early paper associated the term “alien hand” with the impaired ability to recognize self-ownership of a limb (21), this is not presently recognized to be a part of alien hand syndrome owing to the absence of associated involuntary, apparently purposive movements. Nonetheless, the term “alien hand” has sometimes been inappropriately applied to this purely tactile or perceptual disorder (46).
The disinhibited grasp reflex is often seen in alien hand syndrome, but it is also a common feature of either focal cerebral injury (36) or degenerative dementing cerebral disorders without alien hand (143) and normally occurs in infancy. The grasp reflex by itself (ie, without groping or self-opposition) should not be considered alien hand because the disturbance is comparatively simple and is less likely to disrupt patient activities. In such cases the patient does not regard the hand as an independent entity.
Unilateral spontaneous arm levitation is often an aspect of alien hand that is seen in corticobasal degeneration. However, unilateral spontaneous arm levitation may also appear in progressive supranuclear palsy; therefore, distinguishing between these illnesses may be difficult (11). Spontaneous arm levitation does not in itself constitute alien hand because no apparent goal-directed behavior is evident. Spontaneous limb levitation in progressive supranuclear palsy can occur bilaterally, including the legs (43). Cases in which spontaneous arm levitation is associated with denial of limb ownership have been termed alien hand (26) but appear to represent variants of somatoparaphrenia instead. Progressive supranuclear palsy is not associated with alien hand (97), although reports indicating “alien hand” in progressive supranuclear palsy still appear (18). Corticobasal syndrome may be distinguished from progressive supranuclear palsy by stimulus-sensitive myoclonus and somatosensory loss, whereas progressive supranuclear palsy characteristically restricts vertical eye movements and is associated with backwards falling. Limb levitation can also be an early finding of Creutzfeld-Jakob disease (33).
Synkineses are unintended movements that accompany simple voluntary movements, but rather than appearing as the self-interfering movements typical of alien hand, they either mimic the voluntary movement or involve tonic posturing. Bimanual synkineses (139) are upper extremity movements that crudely imitate the contralateral limb. More accurate imitations may be termed “mirror movements” (64). A wide variety of acquired and congenital disorders may be responsible, including the Klippel-Feil syndrome (47) and Kallmann syndrome (150). Mirror movements also occur commonly following stroke (109).
“Associated movements” of hemiplegia (15) are a kind of synkinesis wherein the plegic limb adopts nonspecific increased tone (shoulder abduction, elbow flexion, and finger extension) during yawning or stretching of the unaffected limb. These movements commonly occur in stroke.
A kind of "anti-alien hand" has been reported and termed “avoidant reaction” (41; 40; 89; 107; 70; 52). In avoidant reaction, the patient's fingers extend and the arm rises on the approach of or contact by the examiner rather than grasping at the examiner. This disturbance follows parietal lobe injury and was suggested to occur from a loss of inhibition from frontal and temporal regions that effect withdrawal from environmental stimuli (39).
Phenomena of “alien leg” have been reported, which can include involuntary wriggling of the toes of one foot. This phenomenon has elsewhere been termed “painful legs and moving toes syndrome”; it was first reported as such by Spillane and colleagues (132) and has been reviewed more comprehensively elsewhere (121).
Freezing of gait is a related disturbance whereby patients involuntarily become stuck in their walking, often when they need to increase self-attention for gait stability, as when crossing through a narrow doorway. The patients do not regard their legs as alien to them. Freezing of gait is most often reported in Parkinson disease but is also noted in corticobasal syndrome and other neurodegenerative diseases (95).
Functional neurologic disorder may be mistaken for alien hand (or alien limb) in that involuntary movement or inactivity can occur in one limb episodically. Functional neurologic disorder is the diagnosis when the disturbance is aggravated by the patient’s attention to the limb, there is improved control with the patient’s distraction from the limb, and there is a lack of seeming purpose to the activity (eg, tremor, stiffness).
Associated or underlying disorders
Alien hand is a behavioral disorder that is not associated with a single neurologic disorder. Alien hand is most often found in corticobasal syndrome, stroke, subarachnoid hemorrhage following aneurysmal rupture, or following callosal surgery to relieve persisting seizures. Consequently, other clinical findings that characterize these neurologic disorders can occur with alien hand.
Diagnostic workup
The diagnosis of alien hand may facilitate determining the site of injury and its etiology. When the patient complains of involuntary limb activity, the behavior should be accurately described or demonstrated by the patient or viewed by the examiner. Limb movements that appear to be dissociated from the patient's plan or that are inappropriate for the circumstances should be examined more carefully. Goal-directed or seemingly purposeful activity that the patient denies causing suggests alien hand. Detailed neurologic examination can indicate the subtype of alien hand. Reflexive grasping or absence of spontaneous speech suggests the frontal variant following medial frontal injury. Tactile anomia and ideomotor apraxia of the nondominant hand suggests a callosal lesion. Hemianesthesia suggests that the sensory alien hand variant may be involved, following posterior cerebral hemispheric injury.
Following a thorough neurologic examination, cerebral neuroimaging should be performed to localize the injury and identify its pathology and etiology. In spontaneous alien hand, cerebral infarction is commonly responsible. The frontal variant is often due to rupture of an anterior communicating artery aneurysm and, therefore, angiography should be considered when neuroimaging fails to indicate the site or source of injury. One instance of frontal alien hand behavior was associated with cerebral vasculitis (31). The callosal variant may follow spontaneous infarction but is also frequently seen after surgical corpus callosotomy to treat refractory epilepsy. Corpus callosotomy has been limited to a portion of the callosum to minimize the occurrence of alien hand and other disconnection impairments. The callosal alien hand variant has been observed to follow hypoglycemic encephalopathy due to a pancreatic tumor, which remitted following intravenous glucose and tumor resection (149). Alien hand associated with ipsilateral somatosensory dysfunction should prompt evaluation of the contralateral posterior cerebral hemisphere for infarction or other lesion. It is instructive that alien hand has not been observed in developmental callosal disorders such as callosal agenesis (37). However, some pediatric occurrences of alien hand following acute injury or degenerative brain illness have been described, thus, indicating that young age does not preclude this disorder (65; 131; 136).
Degenerative cerebral disease may also be associated with alien hand in adults, including corticobasal syndrome (62), Alzheimer disease (63), sudanophilic leukodystrophy (78), Creutzfeldt-Jakob disease (74; 62; 108), Marchiafava-Bignami disease (68), multiple sclerosis (98), adult-onset leukoencephalopathy with axonal spheroids (32), and Parry-Romberg syndrome (136). Creutzfeldt-Jakob disease can present with any of the alien hand phenomena, most often with the posterior variant (129). Still other disorders associated with alien hand have included electrical cortical stimulation to map the brain in preparation for seizure surgery, resection and radiation for a brain tumor, migraine, posterior reversible encephalopathy syndrome, and pneumocephalus (66). In a few large series of patients, the incidence of alien hand in corticobasal syndrome has been reported to range from 42% to 50% (83; 62), which may suggest that corticobasal syndrome is the commonest etiology for alien hand. Brain neuroimaging is again indicated. Depending on the clinical presentation, diagnosis may be made through assessing the history, neuroimaging findings, and possibly brain biopsy.
Alien hand may occur as a series of restricted episodes rather than recur frequently. Mechanisms proposed to account for such phenomena have been epileptic seizures (91), transient ischemic attack (04), acute stroke (44), and relapsing-remitting multiple sclerosis (85) because the phenomena were accompanied by other features suggesting these disorders. In such cases, a workup is indicated for assessing epilepsy, cerebrovascular ischemia, or demyelinating disorders of the CNS (electroencephalography, carotid duplex scanning, MRI, etc.).
A possible instance of migraine-induced alien hand has been reported (03). The patient suddenly developed paroxysmal involuntary throwing motions of his left hand that were precipitated by gesturing with the hand. These movements seemed to him to be alien. This disorder coincided with frequent migraine headaches. The alien hand and the headaches resolved by taking topiramate 50 mg a day.
A posture-dependent cause of alien hand has been reported following pontine hemorrhage (72). The patient experienced involuntary grasping of nearby objects but only when he was lying in bed and drowsy. At the same time, he had the illusion that he had a third leg. There was no apparent mechanism common to these two disturbances.
Management
Alien hand generally follows spontaneous acute neurologic injury (eg, stroke) or neurodegenerative disease (eg, corticobasal syndrome) but also follows planned surgical corpus callosotomy for the relief of epilepsy. The spontaneous onset of alien hand is not preventable, other than routine stroke prophylaxis. The reported cases of alien hand following epilepsy surgery are so few that no guidelines have been developed to prevent alien hand. On the other hand, it has been suggested that management of midline cerebral aneurysmal rupture could reduce the persistence of alien hand by avoiding surgical damage to the supplementary motor area, though further study is needed (88).
Rehabilitation for the alien hand syndrome has not been developed (61), which may be due to the uncommon occurrence of the disorder at academic centers. Positioning the alien hand behind the patient’s back may be needed during rehabilitation of other concurrent neurologic disabilities (117). One patient's alien hand interfered so much with daily activities "that his left hand had to be secured to the bed" (133). In the frontal alien hand variant, an oven mitt applied to the errant left hand can completely abolish compulsive grasping (114). Other instances of frontal alien hand responded well to constant visual or tactile contact, including warm water application (58), pocketing (80), or constant visual focus on the hand (106). Perhaps the frontal variant is generally inhibited by constant visual or tactile feedback. This hypothesis is supported by the observation that voluntary rhythmic limb movement can inhibit the frontal alien hand variant (19). Modifications of the patient’s environment to reduce fatigue and nearby distractors potentially could help to control the behavior (57). Occupational therapy approaches that involve concentrating to suppress disinhibited action in frontal alien hand have been found not to be consistently successful or to carry over to activities of daily living (111).
These approaches cannot be considered therapeutic but may be necessary to prevent injury. One study has found that an annoying alarm activated by EMG biofeedback may reduce the time the frontal alien hand spends holding an object (147), but it is unclear that the procedure actually reduces disinhibited grasping itself. A related case study of callosal alien hand showed improved control overreaching for specified objects when the patient either followed verbal commands from the experimenter or generated the commands himself (25). Thus, speech can override abnormal movements in alien hand syndrome. However, it is not yet known whether such an approach may be consistently successful.
Mirror box therapy may improve control over the sensory alien hand variant. A case report found that when the patient’s alien hand was placed behind a mirror, control over the hand improved during a test of bilateral finger tapping when the patient’s normal hand image overlay the location of the alien hand (125). In contrast, when the mirror was covered, the hand became at times uncooperative and resisted placement behind the mirror, and the finger movements became asynchronous. The patient underwent mirror box training while hospitalized, and involuntary control declined. The authors postulate that the visual input of a patient’s normally functioning limb in the location of the abnormal limb can override the dyscontrol. Such mirror box treatment outcomes have been observed also to assist phantom limb pain and other limb-specific neurologic disorders; therefore, mirror box therapy merits further study. However, given the scarcity of alien hand occurrences, it is doubtful that a randomized controlled trial of any interventions can be conducted.
In one case, a patient with compulsive grabbing with the alien hand after a frontal lobe infarction indicated, 5 months after onset, that she could inhibit the behavior through her addressing her hand (134). This suggests that (1) patients may sense an urge to move, which can be self-inhibited, and (2) a possible approach may be to apply psychotherapy.
Pharmacologic approaches. There have been only a few published reports on outcomes from pharmacologic approaches to alien hand. An instance of posterior variant alien hand in a child that followed diabetic encephalopathy improved with both clonazepam and botulinum toxin, though the former treatment was eventually not tolerated (65). Methylphenidate up to 30 mg per day in a double-blind, placebo-controlled fashion was unsuccessful in an instance of frontal alien hand (104). Amantadine 200 mg per day has been reported to benefit utilization behavior in a single case (135) and, therefore, might improve the frontal alien hand variant. Levodopa has been unsuccessful for alien limb in corticobasal degeneration (83).
Outcomes
Because alien hand is relatively rare and sporadic, not inherited, clinical trials have not been possible for treating alien hand. Consequently, it is premature to summarize the outcomes of treatment for alien hand at present. Single case studies show positive responses to specific treatments, which are described above, but without the evidence from randomized controlled trials.
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Dr. Mark of the University of Alabama at Birmingham has no relevant financial relationships to disclose.
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