Hemiballismus

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](B3)

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.(B3)

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.