Hemiballism-hemichorea induced by ketotic hyperglycemia: case report with PET study and review of the literature
- Yuyan Tan†1,
- Xiaoyu Xin†1,
- Qin Xiao1,
- Shengdi Chen1,
- Li Cao1Email author and
- Huidong Tang1Email author
© Tan et al.; licensee BioMed Central Ltd. 2014
Received: 21 March 2014
Accepted: 3 July 2014
Published: 10 July 2014
Hemiballism-hemichorea (HB-HC) is commonly used to describe the basal ganglion dysfunction in non-ketotic hyperglycemic elderly patients. Here we report two elderly female patients with acute onset of involuntary movements induced by hyperglycemia with positive urine ketones. We described the computed tomography and magnetic resonance imaging findings in these two patients, which is similar to that of non-ketotic hyperglycemic HB-HC patients. FDG-PET was performed and the glucose metabolism in the corresponding lesion in these two patients was contradictory with each other. We tried to clarify the underlying mechanisms of HB-HC and explain the contradictory neuroradiological findings in FDG-PET as being performed at different clinical stages.
KeywordsHemiballism-hemichorea Ketotic hyperglycemia Primary diabetes mellitus
Ballism and chorea can result from a varity of conditions, including cerebrovascular, metabolic, neurodegenerative, infectious, toxic, immunologic disorders, as well as non-ketotic hyperglycemia [1–3]. Hemiballism-hemichorea (HB-HC) is commonly used to describe the basal ganglion dysfunction in non-ketotic hyperglycemic elderly patients. It is an unusual clinical entity characterized by continuous, proximal and distal, involuntary movement, particular neuroradiological findings in brain computed tomography (CT) and magnetic resonance imaging (MRI) [3–6]. Usually HB-HC is induced by non-ketotic hyperglycemia [1–4, 7–9], here we report two cases of Chinese elderly women who manifested as HB-HC induced by hyperglycemia with positive urine ketones. We also described CT, MRI and FDG-PET findings in these two patients. They had the particular hyperdensity in the striate area contralateral to the side of HB-HC in CT, and high signal intensity in the putamen in MRI T1-weighted (case 2). The FDG-PET findings in these two patients were contradictory, one patient had decreased glucose metabolism in the lesion while the other patient had hypermetabolism. The mechanism of this syndrome is still not clear. Possible explanations for the pathophysiology and the contradictory radiological findings are also presented.
HB-HC has been described mostly in Asian elderly women patients induced by non-ketotic hyperglecemia [6, 8–11]. Here we report two Chinese elderly female HB-HC patients induced by hyperglycemia with positive urine ketones and normal arterial blood gas analysis. Ketone body includes acetoacetate, β-hydroxy butyric acid and acetone. Urine ketones mainly detect acetoacetate, while blood ketones mainly detect β-hydroxy butyric acid. Although we didn’t detect the blood ketones, the positive urine ketones partially indicated that ketones metabolism was interrupted in these two patients. To the best of our knowledge, only one paper from Dilek Ersil Soysal et al reported an old-age female patient with transient monoballismus during an episode of hyperglycemia with positive urine ketones .
The underlying mechanism for hyperglycemia associated HB-HC is unknown. Possible mechanisms include cerebral vascular insufficiency , hyperglycemic or hyperosmolar insult , microbleeding , interruption of GABA transmission [15–17], autoimmune-mediated inflammatory process , etc. A vascular event is regarded as a possible cause of the striatal lesions based on the sudden onset [19, 20] and the particular neuroradiological findings, high density in striate area in CT and high signal intensity in putamen and/or caudate in T1 weighted MRI. However, demyelination, calcium or other unknown metabolites accumulation have also been regarded as possible causes for the radiological features [21–23].
We used CT and FDG-PET to examine these two patients and MRI for case 2. Both patients showed hyperdensity which is well below that for hemorrhage in the putamen contralateral to the affected side on CT scan. MRI finding in case 2 showed high signal intensity in the putamen contralateral to the side of HB-HC in T1-weighted images. The FDG-PET findings in these two patients were different. In case 1, FDG-PET was performed at 9 days after clinical onset, the involuntary movements was slightly relieved compared with the first day of admission. The rates of cererbral glucose metabolism were significantly increased on the corresponding side. In case 2, the FDG-PET study was performed on 55 days after onset and the symptoms was not well controlled. PET study showed that regional cerebral glucose metabolism was markedly decreased in the corresponding side of the basal ganglion. In Jung Lung Hsu’s report , FDG-PET was performed in three hyperglycemia induced HB-HC patients at 3 weeks, 5 weeks, and 7 months after clinical onset. The rates of cerebral glucose metabolism were markedly reduced in the corresponding lesions. This change provides direct evidence that cerebral glucose metabolism in the lesion site is decreased, which supports the notion of cerebral glucose metabolic failure in the lesions. However, contralateral striatal hypermetabolism was found in FDG-PET scan of chorea caused by other conditions, like primary antiphospholipid syndrome, Contraceptives . Thus, which condition reflects the true pathophysiological metabolic changes in hyperglycemia-induced HB-HC? SPECT studies provided some clues. Seung-Hun Oh et al  reported the results of brain SPECT studies showing cerebral blood perfusion in chorea patients associated with non-ketotic hyperglycemia. Four of them showed hypoperfusion of the basal ganglia on the contralateral side (range = 8 days–4 months), in other four patients, hyperperfusion found in the initial study (range = 6–20 days) had changed to hypoperfusion on the follow-up study. The hyperperfusion of the basal ganglia observed in the earlier clinical course can be explained by increased cerebral blood flow because of vascular autoregulation, the hypoperfusion of the basal ganglia at the later clinical course may be caused by a neuronal metabolic derangement due to hyperglycemia, vascular insufficiency, or both. So in our first patient, PET was performed in comparatively earlier clinical stage (9 days from onset), the rates of cerebral glucose metabolism was increased might due to the increased blood flow and high blood glucose, which is in accordance with the SPECT study. In case 2 and Jung Lung Hsu’s report , PET were performed at the later clinical stage (range > 3 weeks), the decreased cerebral glucose metabolism may be caused by the irreversible damage by metabolic derangement and ischemia of vascular insufficiency. Although we lack the follow-up PET study, we think that whether hyperglycemia is well controlled or not contributes to the changes of metabolism in PET. When the hyperglycemia is well treated, the chorea usually disappears within a few days and might prevent the irreversible damage to the neurons.
The theory of interruption of GABA transmission might provide the molecular mechanism for the involuntary movement. In non-ketotic hyperglycemia, the shift to anaerobic metabolism causes brain to utilize amino butyric acid (GABA) as an alternate energy substrate, which caused the rapid depletion of GABA and ultimately interrupted the GABAnergic transmission [15–17]. GABA is the neurotransmitter responsible for the inhibitory pathway especially in the indirect and direct pathway in basal ganglion. In the indirect pathway, the interruption of GABAnergic transmission from the striatum to the external segments of the globus pallidus (GPe) would cause abnormally increased GPe neuron inhibitory activity on the subthalamic nucleus (STN) [15, 25]. Increased inhibition on STN would decrease its excitatory action on the internal segments of the globus pallidus (GPi), which would lead to decreased GPi neuron inhibitory action on thalamus. The decreased inhibition on thalamus would lead to increased excitatory action on cortex. Besides excitatory STN inputs [15, 26], the GPi neurons also receive inhibitory afferent inputs directly from the striatum in the direct pathway. The imbalance between the indirect excitatory and direct inhibitory pathways ultimately leads to a disinhibition of the motor thalamus and caused the motor cortex over excited [3, 15, 16]. However, patients with positive urine ketones had disrupted ketones metabolism and higher acetoacetate level. As we know, GABA can be synthesized from acetoacetate, so it can not be depleted easily in patients with positive urine ketones. So there might be other mechanisms in the pathophysiology of ketotic hyperglycemia. Another theory first put forward by Carla Battisti et al  in 2009 was that hyperglycemia may directly induce alterations in dopaminergic activity (upregulation of dopamine receptors, decreased DA catabolism) in the striata of predisposed patients and dysregulation of direct and indirect pathways, which ultimately increased the excitatory effect of thalamus on cortex. This theory has been suggested by several studies in animal models [17–29]. HB-HC occurs mostly in elderly female patients indicating female is a predisposing factor. It might be related to postmenopausal oestrogen-induced alterations of GABA or dopamine receptors [3, 30]. For the second patient, the HB-HC symptoms were still present although moderately relieved even after 2 months from onset, which indicated the existence of a mechanism that has long-term effect. Thus, the upregulation of dompamine receptors might be a better explanation to the second patient. Above all, we think both the interruption of GABA transmission, upregulation dopamine receptors and decreased DA catabolism are involved in the pathophysiological mechanism of ketotic hyperglycemia induced HB-HC.
Moreover, in case 1, there was another predisposing factor for the acute onset. On 05 November 2011, the patient had a sudden fall, with hipps and right hand touched the ground. There was no injury of the head and right upper limb. When she stood up by herself, the involuntatory movement started. As these two events were so close, we excluded psychogenic dystonia and posttrauma induced dystonia in this patient. The patient had poor controlled diabtes for more than 10 years, which caused damage to the blood vessel for a long time. The sudden fall became a strong stress to the already weak blood vessel. Moreover, the sudden fall can also be a stress causing sharp elevated blood glucose.
We presented two elderly female HB-HC patients caused by hyperglycemia with positive urine ketones. We conclude that a combination of cerebral vascular insufficiency and metabolic derangements leading to interruption of GABA transmission, upregulation dopamine receptors and decreased DA catabolism, ultimately causing unilateral basal ganglion dysfunction. Although we lack the serial follow-up of PET studies with correlation to the changes of clinical symptoms in these patients, our PET studies combining with the previous PET and SPECT studies provided evidence for the subsequent regional metabolic failure. Ideally, serial follow-up of the PET/SPECT studies in these patients could provide further insights into the actual mechanisms underlying HB-HC.
We thank Chao Wang for his contribution in organizing images at the Department of Nuclear Medicine, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine.
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