Continuing Education Activity

Hemiballismus is a hyperkinetic involuntary movement disorder characterized by intermittent, sudden, violent, involuntary, flinging, or ballistic high amplitude movements involving the ipsilateral arm and leg caused by dysfunction in the central nervous system of the contralateral side. This activity reviews the etiology, evaluation, and management of hemiballismus and highlights the role of the interprofessional team in the identification and treatment of patients with the condition.

Objectives:

• Identify the etiology of hemiballismus medical conditions and emergencies.
• Summarize appropriate evaluation of hemiballismus.
• Outline the management options available for hemiballismus.
• Describe interprofessional team strategies for improving care coordination and communication for patients with hemiballismus and improve outcomes.

Introduction

Hemiballismus is a hyperkinetic involuntary movement disorder characterized by intermittent, sudden, violent, involuntary, flinging, or ballistic high amplitude movements involving the ipsilateral arm and leg caused by dysfunction in the central nervous system of the contralateral side.[1] Hemiballismus falls as the most severe form within the spectrum of chorea. Chorea is an involuntary movement disorder characterized by brief, sudden, spontaneous, non-stereotyped, and dance-like movements in one side of the body. The classic medical school textbook localizes the lesion to the subthalamic nucleus (STN) or the nucleus hypothalamicus/corpus Luys; however, other research also localizes the lesions in other parts of the basal ganglia and caudate nucleus.[2][3]

Etiology

Excessive dopaminergic activity and damage to the pathways of the basal ganglia (hyperkinetic theory) are the basic predominant etiologies of hyperkinetic syndromes. Following are some of the common etiologies of hemiballismus:

• Intracranial hemorrhage[4]
• Stroke (ischemic): the most common cause in patients more than 65-year-old from the small perforating branches of the basilar artery[1]
• Neoplasm
• Head trauma
• Metabolic (e.g., nonketotic hyperglycemic hyperosmolar syndrome in uncontrolled type 2 diabetics)[5]
• Neuroinfectious: although rare, are more common in younger patients
• Tuberculomas[6]
• Toxoplasmosis: from complications of the human immunodeficiency virus (HIV) given its predilection to cause lesions in the basal ganglia
• Neuroinflammatory diseases: such as demyelinating disorders (e.g., multiple sclerosis)[7]
• Paraneoplastic syndromes[8]
• Vasculitis (e.g., systemic lupus erythematosus)[9]
• Toxic: alcohol, heavy metals exposure

Given that chorea syndromes are pathophysiologically a milder spectrum of hemiballismus, etiologies of these have been briefly listed here.[10] Hereditary and primary chorea syndromes can be caused by juvenile and adult-onset, multi-factorial, neurodegenerative, and/or neurodevelopmental disorders such as Huntington disease,[11] Wilson disease, neuroacanthocytosis, dentatorubral-pallidoluysian atrophy, pantothenate kinase-associated neurodegeneration, benign hereditary chorea, paroxysmal choreoathetosis, and senile chorea. Secondary chorea syndromes include metabolic hyperglycemic disorders, dopaminergic drug-induced chorea, Sydenham chorea in acute rheumatic fever in children,[12] vitamin B1/B12 deficiency, toxic exposure, and post-pump choreoathetosis.[13][14][15][16][17]

Epidemiology

The global incidence and prevalence of ballismus and chorea syndromes are difficult to ascertain and are largely unknown; however, it is estimated to be 1 to 2 per 1,000,000. This categorizes hemiballismus as a rare complication of several disorders, as mentioned above. However, for the interested readers, the epidemiology of hereditary and acquired hyperkinetic syndromes can be found in the literature.

Pathophysiology

Hemiballimus is a consequence of damage in the basal ganglia structures involved in the inhibitory pathways. With the decreased excitatory transmission of the globus pallidus internus (GPi) and the disinhibition of the thalamus, it creates an overactivation of the corticospinal and corticobulbar tracts with random firing. Subsequently, efferent innervation is sent to muscles on the contralateral side. Intraoperative monitoring studies show decreased firing of cells in the GPi after a pallidotomy, a surgical treatment to decrease hyperkinetic movements. The neurology-neurosurgical team uses the perioperative rate of firing to assess the efficacy of their targeted intervention.

To better understand the pathophysiology of hemiballismus, a review of the complex basal ganglia inhibitory and excitatory pathways is mandatory. The cortex input is generated and sent to the nuclei of the basal ganglia, with a subsequent output directly to the motor neurons in the frontal lobe and brainstem, leading to planned activation or inhibition of movement. The basal ganglia nuclei consist of the caudate, putamen, globus pallidus, STN, and substantia nigra. The fibers from the globus pallidum convert into a white matter tract called the lenticular fasciculus that forms a bundle called the thalamic fasciculus as it enters the thalamus. The latter is an important relayer of excitatory signals to the motor cortex and somatosensory signals coming from the body. Strokes causing hemichorea-hemiballismus usually localizes to a common functional network with lesions occurring in regions functionally connected to the posterolateral putamen, reinforcing the hyperkinetic movement disorder theory.[2]

• Excitatory or direct pathway: It starts with excitatory glutamate-driven input from the cortex to the striatum (caudate nucleus and putamen). The activation of the striatum sends D1-dopamine receptor driven inhibitory GABAergic signals to the GPi. The inactivation of the GPi allows excitatory glutamate signals to be generated in the thalamus (also called disinhibition of the thalamus), relaying fibers to multiple areas in the motor cortex, including the pre-central sulcus, prefrontal, and supplementary motor areas. Upon activation of these areas, upper motor (efferent) first-order networks are fired, leading to downstream activation of corticospinal and corticobulbar tracts, hence generating movement.

• Inhibitory, or the indirect pathway: It starts in the cortex; however, the activation of the D2-dopamine receptor in the striatum leads to the firing of the globus pallidus externus (GPe). Subsequently, the GPe sends inhibitory signals to the STN. Paradoxically, the STN activates the GPi, which puts inhibition on the thalamus, leading to decreased activation of the cortex, and subsequent blunting of the corticospinal tracts, leading to inhibition of movement.

Histopathology

Given that the large number of disorders that cause hemiballism-hemichorea is exhaustive, it is difficult to mention all the neuropathological findings in this spectrum disorder. A relevant example is hyperglycemia syndrome.[18][19] A stained anteroposterior coronal section of the basal ganglia can show fibrosis and dilation of small perforating arteries. Within them, there is evidence of macrophage infiltration within the small lacunar infarcts. Other inflammatory findings include protein and iron deposition and astrocytic gliosis. Although the neuropathological findings may vary depending on the etiology of the disease, the commonality between them is the anatomical nuclei and pathways affected within the basal ganglia circuit.

History and Physical

Hemiballismus and hemichorea can present with other symptoms besides the motor involuntary, jerky, large amplitude, irregular, appendicular movements on the contralateral side.[1] For stroke or intracranial hemorrhage, cranial nerve signs can include anisocoria, ptosis, facial droop, dysarthria, and headaches. Patients with neoplasm can become altered and disoriented and may be unable to follow commands. Depending on the size, it causes motor and sensory deficits. For younger patients, neuroinfectious and neuroinflammatory etiologies should be explored, with history screening for risk factors, past neurological events, medical co-morbidities, a thorough sexual, and family history. Food, occupational, and travel history should also be obtained. A good medication reconciliation review can provide clues of any drug-induced hyperkinetic disorder. A thorough neurological examination, including cognitive evaluation, cranial nerve, neck rigidity, motor tone, sensory, balance, and gait exam, could also provide clues in the case of rare disorders underlying abnormal movements. Information from family members may be necessary to complete the history.

Evaluation

Given the wide variety of disorders that can cause hemiballismus, a good medical history, and physical evaluation can pinpoint or narrow the diagnosis without requiring any ancillary studies. Old patients with multiple vascular risk factors (e.g., hypertension, diabetes, previous strokes) would need advanced vessel imaging to confirm any hemorrhage or stroke, and if positive, would need a thorough stroke workup.

Thorough routine serum labs, depending on suspected etiology, can include a complete metabolic panel (CMP) and complete blood count (CBC), hemoglobin A1C, serum osmolality, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-nuclear antibody (ANA), extranuclear antibody (ENA), vitamin panel (e.g., B1, B12, etc.), ceruloplasmin, copper level, other heavy metals, drugs of abuse toxicology, HIV antibody screen (if positive opportunistic infection screen), lupus antibodies (C3/C4, double-stranded DNA, anti-histone), antineutrophil cytoplasmic antibodies (ANCA) studies, cryoglobulin, among other immune and infectious markers.

A contrast brain magnetic resonance imaging (MRI), computed tomography angiogram (CTA), magnetic resonance angiography (MRA), or digital subtraction angiogram (DSA) may be used to evaluate for autoimmune pathology, structural abnormalities, or malignancy.

If neuroinfectious (opportunistic bacterial, viral-HIV, or fungal-toxoplasmosis) or neuroinflammatory/paraneoplastic etiology is suspected, a lumbar puncture with extensive cerebrospinal fluid (CSF) basic and advanced studies (oligoclonal bands, CSF index), including flow cytology and cytometry should be obtained. Genetic studies should be sent when indicated, and there is a strong clinical suspicion for a hereditary etiology.

Treatment / Management

Treating the underlying etiology is important, as hemiballismus tends to resolve with time. Therefore, supportive treatment for comorbidities and related complications is important.

Medical Treatment

Medical management includes the use of first and second-generation antidopaminergic drugs, to target D2 receptors (e.g. risperidone, haloperidol, perphenazine, pimozide, chlorpromazine), benzodiazepines (clonazepam), anti-epileptics (topiramate), and tetrabenazine to relieve severe hyperkinetic movements.[20][21][22][23][24][25][26][23][22][21][20]

Surgical Treatment

If patients become refractory to medical management, and the symptoms are severe enough to impair activities of daily living, surgery becomes an option. A stereotactic posteroventral pallidotomy is the procedure of choice and leads to decreased firing of pallidal neurons, leading to relief of the hyperkinetic movements. Micro-recording and intraoperative monitoring are performed during surgery to improve targeted accuracy during the procedure. Intrathecal baclofen has also shown results with post-traumatic hemiballismus.[27] Deep brain stimulation has not been recommended.

Differential Diagnosis

Hemiballistic movements should not be confused with other hyperkinetic movements. Given that hemiballismus and chorea are within a spectrum of hyperkinetic disorders, the history, and physical exam will help narrow the diagnosis and guide the neurologist to order the appropriate ancillary testing, which includes comprehensive serum testing, brain imaging, and at times CSF studies. It is important to tease out the different disorders presenting with hemiballismus, such as:

• Iatrogenic or medication side effects
• Vascular
• Traumatic
• Infectious
• Inflammatory autoimmune
• Cerebral primary or secondary neoplasm
• Vitamin B1 and B12 deficiency
• Toxins, such as alcohol, heavy metals exposure
• Hereditary conditions
• Metabolic

Prognosis

Hemiballismus usually has a good prognosis with remission of symptoms within a few weeks after commencing treatment for those treatable conditions. Unresponsive cases can require surgical intervention.[1]

Complications

Complications from the treatment are rare given hemiballismus is a consequence of damage to the inhibitory pathways in the basal ganglia, and it tends to self-resolve over time with symptomatic treatment. Treating the underlying etiology, especially in acute life-threatening etiologies like an ischemic stroke, is key to avoid further complications and functional deterioration.

Consultations

As hemiballismus can be caused by multiple diseases, it requires interprofessional evaluation and management for promising outcomes. The following are the consultations that may be needed in the management of the underlying disorder.

• Neurology
• Movement disorder sub-specialist
• Neuroimmunology sub-specialist
• Medical genetics
• Neurosurgery
• Oncology
• Infectious disease
• Rheumatology
• Social worker
• Psychologist
• Physical and occupational therapists
• Palliative care

Deterrence and Patient Education

Patients should understand that the causes of hemiballismus may vary depending on the underlying disorder associated with it. Any of the following disorders may present with hemiballismus: traumatic brain injury, stroke, cancer, metabolic, systemic infections, brain infections, autoimmune diseases, genetic disorders, medication side effects, vitamin deficiencies, and toxic substance exposure. Treating the underlying etiology is extremely important. Medical treatment for hyperkinetic movements is sometimes recommended, but surgery is rarely used. Patients should be encouraged that hemiballismus tends to resolve with time. Consultation with the social worker and the psychologist is usually necessary due to the emotional effect that hemiballismus may cause on these patients.

Pearls and Other Issues

• Hemiballismus is a hyperkinetic involuntary movement disorder characterized by intermittent, sudden, violent, involuntary, flinging, or ballistic high amplitude movements involving the ipsilateral arm and leg caused dysfunction in the central nervous system of the contralateral side.
• Global incidence and prevalence are largely unknown, given the wide variety of etiologies but estimated to be 1-2/1,000,000, classifying it as a rare disorder.
• It is caused by excessive subcortical excitatory activity as a result of damage to the inhibitory circuits within the basal ganglia (hyperkinetic theory).
• Etiologies can be vascular, traumatic, neoplastic or paraneoplastic, toxic-metabolic, neuroinfectious, neuroinflammatory, iatrogenic, vitamin deficiency, hereditary-neurodevelopment, or neurodegenerative.
• Pathophysiology of hemiballismus is complex but thought to include decreased excitatory transmission of the GPi and the disinhibition of the thalamus, creating an overactivation of corticospinal and corticobulbar tracts.
• Diagnostic workup includes a thorough history and physical exam, advanced imaging (CT, CTA, MRI with contrast, DSA), extensive serum (CBC, CMP, A1C, ESR, CRP,  ANA, ENA, ANCA, hemoglobin A1C), and CSF analysis, vitamin panel (including B1, B12), drugs of abuse toxicology, sexually transmitted disease screening, among other immune and infectious markers. Genetic studies should be included when indicated.
• Treatment modalities are mostly supportive as the prognosis is good, and it tends to self-resolve when underlying etiology is addressed.
• Pharmacological treatments include first and second-generation antidopaminergic drugs (risperidone, haloperidol, perphenazine), benzodiazepines (clonazepam), anti-epileptics (topiramate), intrathecal baclofen, and tetrabenazine.
• Surgery is considered in refractory cases with severe impairment of activities of daily living. A targeted stereotactic posteroventral pallidotomy is the procedure of choice. Deep brain stimulation is not recommended at this time.

Enhancing Healthcare Team Outcomes

Hemiballismus has a good prognosis with symptomatic and pharmacological treatment, as long as the underlying disorder is addressed. In the case of noncurative etiologies, such as seen in neurodevelopmental, neoplastic, and neurodegenerative disorders, an interdisciplinary team of primary care, specialists, and subspecialty clinicians (general neurology, neurosurgery, movement disorder, neuroimmunology specialist, genetics, oncology, infectious disease, rheumatology, palliative care, social workers, physical/occupational/speech therapists, behavioral health, and nursing coordinators) should work together to coordinate care in accordance to patient-centered goals of care. Particularly in the case of hereditary disorders, genetic counseling to the patient and family members is essential. [Level 5]