Juvenile Huntington disease
Oct. 24, 2022
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Hemiballism is often a challenging movement disorder to manage, especially in severe cases. Outlined herein are some of the salient points that may help the clinician understand better the history, clinical spectrum, causes, pathophysiology, differential diagnoses, diagnostic workup, prognosis, and latest medical and surgical treatment options for hemiballism. A clinical vignette is also provided to illustrate a classic case of hemiballism.
• Hemiballism refers to flinging movements of the upper and lower limbs on 1 side of the body.
• Onset of hemiballism is usually acute, and is most commonly due to ischemic stroke, hemorrhage, autoimmune disorders, medications, metabolic abnormalities (most commonly hyperglycemia), neoplasms, or infections.
• Treatment is usually symptomatic, unless a reversible cause can be identified and corrected (eg, hyperglycemia, infections, drugs, or metabolic abnormalities).
• Drug therapy usually involves use of neuroleptics or antiepileptic agents.
• Medically refractory hemiballismus may be amenable to deep brain stimulation surgery.
"Ballism,” (meaning "to throw" in Greek) refers to violent, irregular flinging limb movements. It constitutes part of the spectrum of chorea (meaning “to dance”) and is a result of proximal muscle contraction. There are several types of ballism, depending on the distribution of movements. The most common form is “hemiballism,” which involves flinging movements of the upper and lower extremities on 1 side of the body. Ballism confined to 1 extremity is referred to as “monoballism.” The term “paraballism” describes ballistic movements in both lower limbs, whereas “biballism” or “bilateral ballism” refers to movements in both sides of the body.
Clinicopathologic and experimental studies in Rhesus monkeys linked lesions of the subthalamic nucleus with contralateral hemiballism. However, hemiballism can also result from lesions of the thalamus, neostriatum, or cerebral cortex. Hemiballism/hemichorea has also been observed in Parkinson disease patients who have undergone subthalamotomy or subthalamic deep brain stimulation (63). However, the ballism or chorea in these patients is usually short-lived and improves with reduction of levodopa dosage. Thus, it is believed that normal individuals (those with a physiologically normal subthalamic nucleus) are prone to ballism with subthalamic nucleus lesioning, whereas Parkinson disease patients (with an abnormal hyperactive subthalamic nucleus) are not.
Typically, hemiballism is of acute onset, but it may evolve over several days to weeks. The patient may be awakened by abrupt onset of violent flinging movements of the proximal parts of an arm or leg on 1 side of the body.
The movements can cause injury of the involved limbs and exhaustion. There may be involvement of the same side of the face with facial and tongue movements. Distally, choreic or athetotic movements of the fingers may be apparent. The movements are said to disappear during sleep, but hemiballism has been noted to persist during lighter stages of sleep.
The involuntary movements may improve with action, but, more frequently, they are worsened by attempts to move.
Bilateral ballism is uncommon and may be associated with dysarthria, dysphagia, and rarely, mutism.
The prognosis depends on the underlying cause. In general, the prognosis of hemiballism due to vascular causes is favorable. If due to other causes, the prognosis depends on the underlying condition. Malignancy and AIDS, for instance, are associated with a poorer outcome. If due to correctible causes like hyperglycemia, parathyroid abnormalities, or certain drugs, the hemiballism is especially responsive to therapy. It is unclear whether the site of the lesion influences the prognosis. Lang reported 2 patients with hemiballism of long duration in which the lesions were outside the subthalamic nucleus (the striatum in particular) and were associated with an ominous prognosis (60). However, others have suggested that lesions outside of the subthalamic nucleus may be associated with a better chance of recovery (47).
In some patients, hemiballism may evolve into a hemidystonia. In others, it transforms into hemichorea before a complete resolution. Complications include exhaustion, bronchopneumonia, and physical or mechanical injuries to the involved limbs.
An 82-year-old hypertensive woman was diagnosed with nonketotic hyperglycemia and was started on an oral hypoglycemic agent. A month later, she developed involuntary, continuous, jerky movements of the right leg that gradually worsened over 3 to 4 days. The movements were partially suppressible for a few seconds and disappeared during sleep. They gradually worsened to the point of causing excoriations and bruising of the right leg and impairment of walking. The patient denied past intake of neuroleptics and any family history of movement disorder.
On examination 11 days after onset of the movements, severe, continuous hemiballism/hemichorea was seen in the right leg. The rest of the neurologic examination was unremarkable. Extensive serologic tests (including blood sugar, electrolytes, liver function tests, thyroid-stimulating hormone, parathyroid hormone, anticardiolipin antibodies, antinuclear antibodies, rapid plasma reagin, blood smear, complete blood count, and erythrocyte sedimentation rate) were normal. Cerebrospinal fluid (CSF) analysis was normal. Brain magnetic resonance imaging (MRI) showed symmetric, increased T1 and T2 signal in the basal ganglia bilaterally, small lacunes in the right and left thalami, and increased T2 signal in the periventricular white matter and subcortical white matter bilaterally. MRI of the cervical and thoracic spine showed normal spinal cord signal.
The patient was treated unsuccessfully with maximum tolerated doses of trihexyphenidyl (6 mg/day), clonazepam (1.5 mg/day), and olanzapine (7.5 mg/day). She was then tried on perphenazine (up to 6 mg/day), with only partial improvement of the leg movements. She was finally placed on risperidone, initially at 1 mg BID, then 1 mg TID 3 days later. She experienced complete resolution of her hemiballismus/hemichorea within 2 days of receiving 3 mg/day of risperidone. Her walking also normalized.
Hemiballism may be due to various etiologies.
Stroke is the most common cause, particularly ischemic infarction affecting the subthalamic nucleus, thalamus, caudate, putamen, centrum semiovale, corona radiata, or cerebral cortex (particularly the frontal lobe or parieto-occipital region) (18; 09; 44; 58; 93). Sometimes transient hemiballism may precede paralysis due to a subcortical stroke (38). Recurrent hemichorea associated with amaurosis fugax has been described due to transient ischemic attacks (64). Acute hemichorea has also been reported from transient ischemic attacks related to atrial flutter (45). Recurrent nocturnal hemiballism has also been described as a sequela of striatocapsular stroke (02). Ischemia involving either the anterior circulation (eg, carotid stenosis) or posterior circulation may have been reported to cause hemiballism, possibly because the subthalamic nucleus is supplied by both the anterior and posterior circulations by way of the anterior and posterior choroidal arteries, respectively. Hemichorea associated with extracranial carotid artery stenosis and thalamic and putaminal hypoperfusion on functional imaging has been described to reverse after carotid revascularization (82). Rarely, hemiballism may result from of a disconnection syndrome of the parietal cortex from the basal ganglia due to stroke (84). One case of hemichorea was described from an ipsilateral frontal cortical infarction (100). Pediatric Moyamoya disease has also been reported to cause hemichoreic movements (53). RNF213-related vasculopathy was reported to cause hemichorea in an elderly woman with contralateral internal carotid stenosis with no acute stroke or lesions on MRI (46).
Hemorrhage, particularly involving the striatum, may also lead to hemiballism. A case of hemichorea secondary to contralateral pontine hemorrhage has also been reported (61). Hemorrhage may be due to hypertension, trauma (with or without subdural hematomas), vascular anomalies (like arteriovenous malformations and venous angiomas), or disseminated intravascular coagulation.
Neoplasms involving the basal ganglia, subthalamic nucleus, pallidosubthalamic pathways, or pituitary gland may also produce hemiballism, including brain metastasis, gliomas, meningiomas, ependymal cysts, and cavernous angiomas, among others (12; 31; 54). Hemichorea may also result from paraneoplastic syndromes due to pulmonary or renal cell carcinoma, or lymphoma (97). Paraneoplastic hemichorea has been described secondary to anti-CV2 antibodies associated with diffuse large B-cell lymphoma or LGI1 antibodies associated with renal cell carcinoma (20; 75).
An elderly patient with polycythemia vera presented with acute-onset hemichorea and frontal lobe syndrome, with brain imaging showing no vascular pathology in the basal ganglia or frontal region (39).
Brain infections may also lead to hemiballism, including tuberculous meningitis, tuberculoma (78), acquired immune deficiency syndrome (AIDS) (95), toxoplasmosis (26), cysticercosis, and Creutzfeldt-Jacob disease (67). Two pediatric cases of varicella-induced vasculopathy leading to acute hemichorea have been reported, with cranial MRI showing vasculitis and ischemic lesions in the basal ganglia (22). Two cases of acute and reversible hemichorea-hemiballism were described after COVID-19 vaccination with the AstraZeneca vaccine (AZD1222), which improved after a short course of corticosteroids (66). Based on the steroid-responsiveness of the 2 cases and normal brain scans, an inflammatory mechanism was proposed.
Autoimmune disorders, like systemic lupus erythematosus, antiphospholipid syndrome, multiple sclerosis, or Sydenham chorea, may produce hemichorea/hemiballism (12). Nonketotic hyperglycemic crisis in type 2 diabetes mellitus has also been reported to present with persistent chorea/ballism and is theorized to have an ischemic or autoimmune basis as well (01; 88). Hemichorea-hemiballism has been reported to be the initial presentation of type 2 diabetes (83). Hemichorea-hemiballism from type 2 diabetes may be worsened by episodes of hypoglycemia (85). Reports of chorea/ballism from ketotic hyperglycemia from type 1 diabetes mellitus are rarer and tend to be seen in younger individuals (07). Cerebrospinal fluid in nonketotic hyperglycemia-associated hemichorea/hemiballism may show an elevation of protein concentration, increased IgG, elevated IgG index or 24-hour intrathecal IgG synthesis rate, thus suggesting that inflammation within the central nervous system may participate in its pathogenesis (99). A 14-year-old girl with a history of Sydenham chorea presented with recurrence of chorea after contracting COVID-19 (106).
Various drugs can cause hemiballism. Neuroleptic medications, used for psychiatric reasons or for nausea, may lead to tardive dyskinesias, which can be choreic or ballistic in nature. Oral contraceptives have a tendency to bring out latent hemichorea/hemiballism, especially in individuals with a history of Sydenham chorea (15). In some, hemichorea may develop from oral contraceptive use despite the absence of predisposing factors like lupus or antiphospholipid antibodies (96). Phenytoin intoxication can lead to bilateral ballism. Bilateral ballism was noted in an epileptic patient receiving 200 mg/day of lamotrigine; the ballism completely resolved on discontinuation of the drug (103). One case of gabapentin-induced hemichorea was also reported, with cerebral hypoperfusion observed on functional imaging in the contralateral basal ganglion (57). Chorea was noted in bilateral upper limbs and face in a woman with brain metastasis with seizures who was treated with IV levetiracetam (104). One case of sertraline-induced hemichorea was discovered 1 week after administration of sertraline for depression. All involuntary movements gradually stopped upon discontinuation of sertraline (40). Levofloxacin was found to induce hemichorea-hemiballism in a patient with a previous thalamic infarction (08). Memantine was discovered to cause chorea and dystonia in an elderly patient with Alzheimer disease who had an accidental overdose of memantine when switching from immediate release to sustained release memantine. All symptoms stopped once memantine was discontinued (11).
Overuse of the antitussive cloperastine was reported to induce hemichorea (19). Reversible hemichorea has also been reported to occur with valproate use (91). Two pediatric cases of ifosfamide-induced hemiballism with encephalopathy were described that improved with administration of methylene blue and thiamine (04).
Parkinsonian syndromes, particularly Parkinson disease, multiple system atrophy (94), or striatal degeneration (13), may be associated with hemiballism. In Parkinson disease patients, this is usually seen in advanced disease and chronic levodopa treatment. Parkinson disease patients who have undergone stereotactic thalamotomy (24) or subthalamotomy may also develop iatrogenic hemiballism (16). Subthalamic deep brain stimulation in Parkinson disease may result in transient hemiballism (63). Chorea was discovered to be a side effect in a patient who underwent deep brain stimulation for treatment of obsessive-compulsive disorder. Electrodes initially implanted in the anteromedial portion of the STN alleviated compulsive behaviors, but caused large choreatic movements of the limbs. Motor side effects were reduced upon transfer of electrodes to the ventral capsule/ventral striatum region, while still retaining therapeutic effect (72).
Stimulation-induced hemichorea has also been described in a patient with essential tremor who underwent ventral intermedius deep brain stimulation but with the lead being situated too ventrally (90).
Children with static encephalopathy may develop recurrent episodes of generalized, violent ballism that are provoked by relatively minor infectious illnesses or surgical procedures (10). Hemichorea has also been described in Wilson disease (50) and in children with nutritional vitamin D deficiency (34). Hemichorea has been described in a patient with tuberous sclerosis complex and unilateral basal ganglia atrophy (33).
Other causes of hemichorea and hemiballism include idiopathic hypoparathyroidism (28), hyperthyroidism (69), ventriculoperitoneal shunting (03), and migrainous aura (102). Hypoglycemia-induced acute-onset hemichorea was described in an elderly type 2 diabetic patient with Fahr syndrome and basal ganglia calcifications who developed hypoglycemia following insulin overtreatment (81).
Classically, ballism has been associated with an ischemic or hemorrhagic lesion of the contralateral subthalamic nucleus. However, neuroimaging studies have shown that lesions of areas outside of the subthalamic nucleus (eg, caudate or putamen) are found more often than previously thought (98). Furthermore, ipsilateral putaminal lesions have been noted in hyperglycemia-associated hemichorea-hemiballism (36). There seems to be some somatotopic organization within the subthalamic nucleus with posterior subthalamic nucleus lesions resulting in monoballism of the contralateral lower limb (76). Ballism from pallidal lesions usually involves the external segment. Clinicopathological studies by Carpenter and colleagues (14) showed that hemiballism results if at least 20% of the subthalamic nucleus is involved and is abolished with lesioning of the internal segment of the globus pallidus. Hemiballism is believed to be due to a lack of tonic inhibition of the lateral globus pallidus by the putamen, leading to a greater inhibition of the subthalamic nucleus and lack of excitation of the medial globus pallidus; this ultimately results in disinhibition of the thalamus and the motor cortex. This may not hold true for every case of ballism and does not explain why a lesion of the presumably underexcited or inactive medial globus pallidus would abolish hemiballism in experimental situations. Also, this model does not explain the rare occurrence of hemiballism with lesions of the lateral pallidal segment.
Neuropathological examination of a patient who suffered from hemiballism from nonketotic hyperglycemia showed presence of activated microglia on immunohistochemistry in the subthalamic nucleus contralateral to the hemiballism (65).
The neurochemistry of hemiballism is also unclear. It is possible that it is associated with dopaminergic hyperactivity, as suggested by responsiveness to dopamine-blocking agents (32) and elevation of cerebrospinal fluid homovanillic acid levels in patients with hemiballism. Injections of GABA antagonists into the subthalamic nucleus or in different regions of the lenticular nucleus may produce hemiballism, suggesting the role of GABAergic neurons (21). Using transcranial magnetic stimulation, patients with hemichorea-hemiballism related to uncontrolled diabetes were determined to have increased long interval intracortical inhibition during muscle activation but not at rest, as well as increased silent period duration, thus suggesting increased GABA-B receptor-mediated inhibitory activity in the contralateral motor cortex (62). The efficacy of the selective serotonin reuptake inhibitors in controlling hemiballism implies that serotoninergic neurons may also be involved (77).
The epidemiology of ballism in the general population is unknown. In a large movement disorder clinic, 21 cases of hemiballism were seen out of 3084 patients (23).
The modification of risk factors for ischemic and hemorrhagic stroke (eg, hypertension, heart disease, hyperlipidemia, or smoking) will help reduce the incidence of stroke-related hemiballism. Correction or treatment of potential causes of hemiballism, including hyperglycemic crisis, hypoparathyroidism, or infections, or avoidance of offending substances or medications may help prevent hemiballism.
Ballism needs to be differentiated from partial seizures, myoclonus, and other involuntary movements. Partial motor seizures cause relatively rhythmic clonic jerking of the affected body part. Myoclonus refers to quick, lightning-like jerks and is rarely unilateral. Negative myoclonus (asterixis) may be unilateral in structural brain lesions but should be easily distinguishable from hemiballism because of the characteristic loss of tone. Hemichorea may coexist with hemiballism, and these 2 are considered to be part of the spectrum of choreic disorders.
In the setting of acute hemiballism, a brain imaging study (either CT or MRI with contrast) should be performed to look for subthalamic nucleus lesions (or other basal ganglionic or thalamic lesions). In the absence of hemorrhage, areas of abnormal contrast enhancement may suggest tumor, infection, inflammation, or active demyelination. In hemiballism-hemichorea associated with nonketotic hyperglycemia, putaminal hyperintensity is noted on T1 without diffusion restriction on diffusion weight imaging (DWI); putaminal hypointensity can also be seen without phase shift on susceptibility weight imaging (SWI). These findings are compatible with either pathological mineralization or petechial microhemorrhages or protein denaturation (06). T1 hyperintensity may be from the protein hydration layer inside the cytoplasm of swollen gemistocytes appearing after acute cerebral injury; these astrocytes express metallothionein with zinc, which is thought to be the cause of asymmetric hypointensity of the posterior putamen on SWI (17). Putaminal changes on brain imaging may also be noted before the onset of clinical symptoms (73). When a brain MRI fails to show the responsible lesion in the setting of acute hemichorea, evaluation of cerebral blood flow using single-photon emission computed tomography (SPECT) may detect hypoperfusion in the subthalamic area or thalamus (86). Hyperglycemic hemichorea has also been associated with marked hypometabolism on 18F-fluorodeoxyglusose (FDG) positron emission tomography (PET) in the contralateral basal ganglia (56). A case of hyperglycemic hemichorea was described as not only being associated with increased T1 signal intensity in bilateral lenticular nuclei but also with dopamine transporter (DaT) imaging abnormalities consisting of absent uptake in the putamina bilaterally and moderately diminished uptake in the right caudate (27). Given the absence of parkinsonism, it was theorized that the swollen astrocytes noted in hyperglycemic chorea-ballism may be the structural basis for the falsely positive DAT scan.
Routine blood chemistry should include fasting and postprandial blood sugar determinations and measurement of serum calcium and phosphorus. In appropriate patients, antiepileptic drug levels should be obtained. In patients with hemiballism and a history of intravenous drug abuse, multiple sexual partners, homosexuality, or immunocompromised state (eg, malignancy), one should look for evidence of AIDS and AIDS-related infections or neoplastic processes. In a child with ballism, one should look for evidence of previous streptococcal infection and active carditis (to rule out Sydenham chorea).
Serum antinuclear antibodies, anticardiolipin antibodies, and lupus anticoagulants should be tested in young individuals (to rule out the antiphospholipid syndrome), particularly in women with a history of recurrent spontaneous abortions, recurrent deep venous thrombosis, or other thrombotic events. Antibasal ganglia antibodies may also be detected in some patients with choreic disorders, especially those with a history of Sydenham chorea or oral contraceptive use, thus suggesting an immunological basis for the abnormal movements (70).
Electroencephalography (EEG) is usually normal, though periodic lateralized epileptiform discharges (PLEDS) was reported in a case of hemiballism-hemichorea related to hyperglycemia (101).
Proper management hinges on the correct identification and treatment of the underlying cause. Hemiballism due to destructive lesions is treated symptomatically.
The most effective drugs are those that block the postsynaptic dopamine D2 receptors. Traditional neuroleptics, like haloperidol or perphenazine (15), have been the most common drugs used to treat hemiballism. Not uncommonly, withdrawal of such drugs results in reemergence of the hemiballism, suggesting that the movements are only being suppressed symptomatically. Atypical antipsychotic agents, like clozapine (92) or risperidone (32), olanzapine (79), or quetiapine (unpublished observation) may be as effective as traditional neuroleptics but may be associated with less incidence of extrapyramidal side effects. Tardive dyskinesia may also develop from chronic risperidone usage, particularly at doses higher than 6 mg/day. Dopamine depletors, like tetrabenazine and reserpine, have been used with some success (80). Two novel selective vesicular monoamine transporter 2 (VMAT2) inhibitors, valbenazine and deutetrabenazine, have longer half-lives and better side effect profile than tetrabenazine, including less somnolence, parkinsonism, depression, and akathisia (49). Valbenazine was approved and released in 2017 for tardive dyskinesias (52). Unlike tetrabenazine, which is metabolized to α-isomers and β-isomers (the latter has minimal dopamine D2 receptor antagonism properties), valbenazine only has the (+)-α-isomer. Deutetrabenazine, a deuterated form of tetrabenazine, was also released in the first half of 2017 for Huntington chorea and approved for release in the second half of 2017 for tardive dyskinesias (05).
Antiepileptic agents may be useful in some patients with hemiballism. Sodium valproate has had inconsistent benefits in hemiballism patients (87) and may rarely cause choreiform movements in patients with severe epilepsy and brain damage (59). Gabapentin was noted to be effective in controlling hemichorea/hemiballism due to stroke (55). Topiramate was reported to be effective in the management of refractory hemichorea/hemiballism, either of vascular or metabolic etiology (30). A case of vascular hemichorea/hemiballismus was also reported to respond significantly to topiramate (41). Levetiracetam has also been noted to be efficacious in alleviating hemiballismus related to subthalamic hemorrhage (68).
Progabide, a GABAergic agent (42) and dimethylaminoethanol, which increases acetylcholine, have been reported to benefit patients with hemiballism (48).
Sertraline, a selective serotonin reuptake inhibitor, has also been reported to alleviate hemiballism (77).
A case involving a patient with diabetic chorea demonstrated successful reduction of motor symptoms through a combination of gabapentin and levodopa (105).
Repetitive transcranial magnetic stimulation of the motor cortex was successfully used to alleviate poststroke hemichorea, though the benefit was reported to last only 24 hours after each session of stimulation (25).
Patients with hemiballism unresponsive to oral medications may respond to botulinum toxin injections (29). Such therapy, however, results in limb weakness, and the effect only lasts 3 months on an average.
Intrathecal baclofen was noted to be effective in controlling severe lower limb ballism in a patient with posttraumatic hemiballismus and dystonia that was unresponsive to various oral medications, botulinum toxin injections, and phenol injections (37).
Patients who are unresponsive to medications or are sensitive to their side effects may be candidates for stereotactic lesioning procedures like thalamotomy or pallidotomy (89) or deep brain stimulation of the thalamus or globus pallidus (71). Microelectrode recordings of a patient with diabetic hemichorea-hemiballism showed abnormalities in the globus pallidus interna consisting of irregular firing with pauses (43). This may explain why pallidotomy or pallidal stimulation may help hemichorea-hemiballism, as those procedures lead to blocking of the irregular choreogenic neuronal firing in the globus pallidus interna.
A case of persistent and medically refractory hemichorea/hemiballism from diabetes was also reported to have a long-term response to contralateral thalamic deep brain stimulation with the ventral oralis anterior and posterior nuclei as targets (74).
Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been used successfully with rehabilitation therapy to alleviate persistent hemichorea/hemiballism after nonketotic hyperglycemia (51).
Rarely hemichorea may be the manifestation of chorea gravidarum; this is particularly true for those with a history of Sydenham chorea (15). However, no information is available about preexisting hemiballism/hemichorea and the effects of pregnancy.
A patient with restless legs syndrome who suddenly discontinued use of tramadol reported severe, choreatic hyperkinesia, which was immediately alleviated with intravenous fentanyl (35).
Virgilio Gerald H Evidente MD
Dr. Evidente of the Movement Disorders Center of Arizona received honorariums from Adamas, Ipsen, Medtronic, Neurocrine, Teva, and UCB for speaking engagements; research support from Acadia, Acorda, Lundbeck, Neuraly, Pharma Two B, Revance, and Sunovion as an investigator; and honorariums from Amneal, Kyowa Kirin, Revance, Sunovion, and Teva for consulting work.See Profile
Robert Fekete MD
Dr. Fekete of New York Medical College received consultation fees from Acadia, Acorda, Adamas, Amneal/Impax, Kyowa Kirin, Lundbeck, Neurocrine, and Teva.See Profile
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