“Diabetic striatopathy”: clinical presentations, controversy, pathogenesis, treatments, and outcomes

Diabetic striatopathy (DS) is a rare medical condition with ambiguous nomenclature. We searched PubMed database from 1992 to 2018 for articles describing hyperglycemia associated with chorea/ballism and/or neuroimages of striatal abnormalities. Descriptive analysis was performed on demographic/clinical characteristics, locations of striatal abnormalities on neuroimages, pathology findings, treatment strategies, and outcomes. In total, 176 patients (male:female = 1:1.7) were identified from 72 articles with mean age 67.6 ± 15.9 (range, 8–92). Among them, 96.6% had type 2 DM with 17% being newly diagnosed. Average blood glucose and glycated hemoglobin concentrations were 414 mg/dL and 13.1%, respectively. Most patients (88.1%) presented with hemichorea/hemiballism. Isolated putamen and combined putamen-caudate nucleus involvements were most common on neuroimaging studies with discrepancies between CT and MRI findings in about one-sixth of patients. Unilateral arm-leg combination was the most frequent with bilateral chorea in 9.7% of patients. Chorea and imaging anomalies did not appear concomitantly in one-tenth of patients. Successful treatment rates of chorea with glucose-control-only and additional anti-chorea medications were 25.7% and 76.2%, respectively, with an overall recurrence rate being 18.2%. The most commonly used anti-chorea drug was haloperidol. To date, four out of six pathological studies revealed evidence of hemorrhage as a probable pathogenesis.


Definitions.
In the present study, diabetic striatopathy (DS) was defined as a hyperglycemic condition associated with both or either one of the two following conditions: (1) chorea/ballism; (2) striatal hyperdensity on CT or hyperintensity on T1-weighted MRI as previously reported 9,12,15 .
Three anatomical regions were used in the description of the locations of neuroimaging anomalies in the basal ganglia, namely, caudate nucleus, putamen, and globus pallidus. The terms "mismatch" and "incompatibility" were used in this study to describe the discrepancies between non-enhanced CT and T1-weighted MRI findings. While mismatch between CT and MRI results was defined as the complete absence of anomaly in basal ganglia on one but not the other study, incompatibility referred to the difference in locations of striatal anomalies between the two imaging modalities.
In terms of symptom presentation, we documented chorea involvement in four main body regions: face, trunk, arm, and leg. Furthermore, pre-treatment interval of chorea was defined as the estimated duration between the onset of chorea and treatment, while recovery time referred to the time period from the initiation of treatment to complete resolution of chorea. Regarding treatment outcomes, successful treatment (i.e., complete response) referred to patients with documented complete resolution of chorea or residual minor chorea after treatment, whilst partial response indicated those with documented partial or moderate-degree resolution of chorea following treatment in the present study. For determining the incidence of chorea recurrence, only patients with a minimum of one-month follow-up were included. For comparison between neuroimaging anomalies and clinical manifestation of chorea, the term "inconsistency" represented the condition in which the clinical presentation of chorea did not accompany striatal abnormality on neuroimaging study or vice versa. Ineffective medical treatment against chorea was defined as no response or only slight response after drug administration based on documentation in the reports. In addition, for interpretation of pathological findings, we defined time-delay as the estimated time interval between positive neuroimaging findings and biopsy/autopsy.

Statistical analysis.
A database on patient's information was created using the Excel ® program in which descriptive analysis was performed with categorical variables expressed as percentage and continuous variables shown as means with standard deviation. Non-normally distributed variables (i.e., durations) were shown as medians and 95% confidence intervals (CIs). Fisher's exact test was used to determine the significance of correlation between CT and MRI findings as well as the recurrence rate of glucose-control-only group and that of additional anti-chorea medication group. A probability value of less than 0.05 was considered statistically significant.

Sensitivity of ct and MRi to detecting DS-associated chorea and inconsistency between symp
Scientific RepoRtS | (2020) 10:1594 | https://doi.org/10.1038/s41598-020-58555-w www.nature.com/scientificreports www.nature.com/scientificreports/ with chorea, the current study showed a sensitivity of 95.33% and 78.86% for MRI and CT, respectively. The inconsistency rate of CT scan (n = 126) and MRI (n = 153) was 20.6% (26/126) and 4.6% (7/153), respectively. The overall inconsistency rate (i.e., chorea with negative imaging finding on one or both imaging modalities or vice versa) was 9% (16/176) which included 12 patients presenting with chorea without striatal involvement on imaging studies (6.8%, 12/176) and four patients showing striatal involvement without the clinical manifestation of chorea (2.3%, 4/176). treatment with glucose control only versus addition of anti-chorea medications and outcomes and alternative therapeutic approaches. To investigate the therapeutic effects of glucose-control-only and anti-chorea treatments against chorea and symptom recurrence, the patients were retrospectively divided into two groups according to their treatment outcomes, namely, those receiving glucose control only and those with the addition of anti-chorea medications. In our study, 26.7% (46/172) of patients received only glucose control and 73.3% (126/172) received glucose control with the addition of anti-chorea medications (Fig. 3).
Successful treatment was achieved in 25.6% (44/172) of patients receiving glucose-control-only treatment during hospitalization. There were two other patients showing either partial response (n = 1) or no response (n = 1) who did not receive anti-chorea medication because of loss to follow-up (n = 1) or mortality (n = 1).

Discussion
Although the disease of "hemiballism" was first described six decades ago 77 , the term "diabetic striatopathy" (DS) was introduced merely a decade ago to denote the condition in which there is a combination of striatal hyperintensity on T1-weighted MRI and contralateral movement disorder in diabetic patients 9 . There was a large time gap before the term being expanded in recent years to also include those presenting with either imaging anomalies 15 or chorea 12 . Although DS is a well-documented etiology of chorea/ballism, most previous reports on DS did not provide detailed descriptions on the presentations. The occurrence of chorea/ballism is mostly due to   75 . Beside DS, other etiologies of chorea/ballism include cerebrovascular, autoimmune, toxic, malignant and infectious illness 5 . The ambiguity in definition of DS and the different terms used to describe the condition may have led to underestimation of the prevalence of the disease. The present systematic review is the first to address the inconsistency between symptom and neuroimaging presentations, mismatch and incompatibility between CT and MRI findings, resolution time of neuroimaging anomalies, the effectiveness of different treatment strategies, symptom recurrence incidence, and disease progression-associated pathological changes.
To date, there have only been a few original articles in the literature, including two relatively large series. While one study reported 20 patients within four years at one institute 14 , the other described 25 patients within six years at five hospitals 78 . Both reported slight female predominance and susceptibility of the elderly to DS as in the present study. Compared to an earlier meta-analysis on DS investigating only adults with hyperglycemic hemichorea 5 , the current study expanded to childhood and enrolled four patients below 18 years of age with the youngest being eight years old. In addition, though Asian patients were most commonly reported in previous studies, the present study showed that there have been an increasing number of reports from Europe, North and Latin America.
DS typically happened in patients with long-standing poor control of DM which was further confirmed by remarkable elevation of blood glucose and glycated hemoglobin level in our study, and it could even occur after correction of hyperglycemia 17 . Consistently, the majority of DS patients (96.6%) in the current study had type 2 DM including one sixth with newly diagnosed diabetes, suggesting that DS could be the first presentation of DM. Regarding the association between DS and ketosis, a large majority (81.7%) of patients with documented ketone status in the present study were not ketotic, compatible with the term "hyperglycemic non-ketotic hemichorea/ hemiballism". On the other hand, ketosis in the remaining 18.3% patients implied that occurrence of DS is not restricted to non-ketotic patients. The susceptibility of DS to non-ketotic hyperglycemic condition may arise from the underlying pathophysiology of chorea. In non-ketotic hyperglycemic status, brain metabolism shifts to the alternative anaerobic pathway in Krebs cycle that leads to rapid depletion of gamma-aminobutyric acid (GABA), resulting in disinhibition of subthalamus and basal ganglia that causes hyperkinetic movements in DS patients. At the other end of the spectrum, in ketosis, GABA can be resynthesized by using acetoacetate produced in the liver to prevent its reduction, thereby explaining the less common occurrence of DS in diabetic ketoacidosis 5,12 .
The results of the current study showed that chorea of DS mostly involved unilateral limbs with only 9.7% of bilateral involvement. Before onset of chorea, there were some prodrome symptoms including chest pain 21 , shoulder pain 24 , headache 40 , gait imbalance 49 , hemiparesis 49 , lethargy 61 , stiffness 31 , vertigo 70 , dizziness 17,34 , confusion 69 and coma 11 . The presentations of the involuntary movements in DS varied among patients. They could start abruptly or insidiously from low to high amplitude, and manifest intermittently or continuously. Cases with chorea progressing from upper to lower extremities 6,66,70 were more common than lower to upper extremities 19 . In addition, most patients with chorea worsened during nervousness and disappeared after sleep. Only two reported cases showed no suppression of chorea during sleep 23,30 . Although the majority of DS manifested with chorea/ hemichorea, there were four patients without chorea who presented with conscious disturbance 15,66 , seizure 66 , limb weakness 54 , dysarthria and dysphagia 54 .
Compatible with the findings of previous reports 5 , the most common pattern of striatal anomalies of DS was isolated putamen involvement, followed by combined caudate nucleus-putamen involvement. Concomitant occurrence of anomalies in all three striatal components was also noted in over one-fourth of all cases ( Table 1). The reason for striatal vulnerability to DS remains unclear. In terms of body regions affected, despite the highest frequency of extremity involvement in the order of arm-leg, arm-leg-face, and isolated arm, there were two reported cases with isolated facial hemichorea presenting with oral dyskinesia and grimacing 70,79 . No significant association was noted between the body region involved and the location of striatal anomaly.
CT and MRI were the two commonest imaging modalities to detect striatal anomalies of DS. Despite the highly significant correlations between their findings, there was around one sixth of mismatch (17.5%) and incompatibility (14.6%) between results of CT and MRI in our study. With regard to mismatch between findings from the two imaging modalities, the current study revealed that MRI is more sensitive to the detection of DS-associated striatal anomalies as it demonstrated striatal lesions in patients who exhibited negative CT results, whilst there was no positive finding on CT scans in patients showing no abnormality in all three regions of basal ganglia on MRI. However, our results were only based on the included studies. Considering the possibility that CT and MRI may detect anomaly in different regions of basal ganglia (i.e., incompatibility, Fig. 2), CT is still indicated for patients with negative MRI findings.
In view of the correlation between imaging findings and clinical symptoms, the present study not only demonstrated a higher sensitivity of MRI than that of CT to the detection of hyperglycemic chorea (95% vs. 79%, respectively) but also revealed a much lower inconsistency rate (4.6%) compared with that of CT (20.6%). Therefore, the findings suggested that MRI may show better correlation with the presence of chorea compared with CT. In addition, the follow-up striatal abnormalities of CT images seemed to resolve faster than those of MRI. The shortest follow-up resolution time on CT was 10 days compared to 60 days on MRI in our study, implying that MRI may be a more accurate tool for tracing the resolution of striatal anomalies in follow-up studies. Furthermore, the current study also revealed an increase in signal intensity of the striatal hyperintensity during serial follow-ups on MRI which was not shown on CT scans, indicating that striatal hyperintensity might reach a maximum level on an average of 3 months (93.6 days) after which the intensity began to decline.
Although a wide variety of mechanism can lead to striatal hyperintensity on T1-weighted MRI including hypertensive hemorrhage, calcification, genetic diseases (e.g., Tay-Sachs disease, tuberous sclerosis, neurofibromatosis, Fahr disease), metabolic disorders (e.g., Wilson's disease, hypoglycemic coma, chronic hepatic encephalopathy), toxicity (e.g., manganese toxicity, carbon monoxide poisoning), and brain ischemia (e.g., lenticulostriate infarction, postcardiac arrest encephalopathy), the striatal lesions are mostly bilateral except in the case of hypertensive hemorrhage 21 . One of the distinctive features of DS-associated striatal anomaly to differentiate it Scientific RepoRtS | (2020) 10:1594 | https://doi.org/10.1038/s41598-020-58555-w www.nature.com/scientificreports www.nature.com/scientificreports/ from hypertensive hemorrhage is the absence of mass effect and the sparing of the internal capsule 65 . This unique imaging finding, when combined with hyperglycemia and the presence of chorea as noted in the majority of patients in the present study, is pathognomonic of the condition.
To date, there have been four hypotheses to explain the pathogenesis underlying the observed striatal anomalies on neuroimages, namely petechial hemorrhage 64 , mineral deposition (i.e., calcium or magnesium) 13 , myelin destruction 56 , and infarction with astrocytosis 13,75 . Researchers initially attributed striatal anomalies to petechial hemorrhage based on the observation of hyperdensity on CT and hyperintensity on MRI strongly suggestive of the presence of hemorrhage and methemoglobin, respectively 80 . Other previous studies utilized different imaging modalities in an attempt to elucidate cellular function and perfusion status of the affected region. For instance, studies from diffusion-weighted MRI 72 and susceptibility weighted MRI 47 suggested hyperviscosity with cytotoxic edema and deposition of paramagnetic material, respectively. Positron-emission tomography (PET) studies demonstrated marked decrease in glucose metabolism of the lesioned basal ganglia 17 , while single-photon emission CT (SPECT) revealed mostly hypoperfusion in the corresponding region 71 . A recent study using magnetic resonance angiography revealed oozing around the basal ganglia lesion 15 .
Unlike radiological studies, pathological analysis could shed direct light on the pathogenesis of DS-associated striatal lesions. Although myelin destruction may appear as hyperintensity on T1-weighted MRI, there was no evidence suggesting its presence according to the six available pathology reports. However, reactive astrocytosis documented in five pathology reports 9,13,64,73,76 and abundant gemistocytes in another biopsy 75 may partially explain the striatal hyperintensity on T1-weighted MRI but not hyperdensity on CT. On the other hand, there were only two pathology reports showing some calcium deposits 73 or punctuate calcification 13 which, however, could not account for the observed resolution on subsequent neuroimaging studies. In contrast, microvascular hemorrhage may be a probability based on the findings of four pathological analyses showing hemosiderin-contained macrophages 73 , microhemorrhage 13 , extravascular hemosiderin deposits 64 , and erythrocytes extravasation 9 , respectively.
The mainstay of DS treatment is control of hyperglycemia with proper hydration to correct the underlying metabolic imbalance 12 . The present study revealed that although chorea could be successfully treated with glucose control only in one-fourth of the patients, the majority needed additional anti-chorea medications for symptom control. There are four main categories of anti-chorea medications, namely antipsychotics, GABA-receptor agonists, selective serotonin reuptake inhibitors and dopamine-depleting agents 12 . The current study showed that haloperidol was the most common monotherapeutic agent against DS-associated chorea, followed by tetrabenazine, risperidone and clonazepam. Other anti-chorea medications included tiapride, quatiapine, pimozide, diazepam and vaproate. Combined regimens were also sporadically documented. For patients with intractable chorea, more aggressive approaches may be indicated. The present study demonstrated a high degree of effectiveness of anti-chorea medications for chorea relief after failure of glucose control for resolving symptom.
The lack of significant difference in treatment intervals both between the insulin-control-only group and the additional anti-chorea medication group as well as between the complete response and poor response groups suggested that the timing of treatment intervention may not be a critical contributor to patient outcomes which appeared to depend more on the severity of the underlying condition. Therefore, the significantly shorter recovery time of the insulin-treatment-only group than that of the additional anti-chorea medication group may reflect a less severe disease in the former compared with that in the latter. Taking into account the possibility of recurrent chorea even after the resolution of striatal anomaly 40 , the relatively high overall recurrence rate of close to 20% highlights the need for regular follow-ups regardless of the neuroimaging findings.
There were several limitations to the present study. First, the relatively small number of studies precluded reliable comparison and elucidation of the effectiveness of different medications and alternative treatment approaches. Second, because the time between glucose control failure in chorea relief and the implementation of anti-chorea medications was not mentioned in most studies, the differences in severity of symptoms between the two groups and the effectiveness of the two treatment strategies could not be compared. Third, most included studies merely reported the presence of ketone bodies in urine and/or blood as a diagnostic tool for ketosis without mentioning the exact level so that the severity of ketosis could not be determined. Fourth, the limited number of pathology reports available could not shed enough light for understanding DS-induced striatal pathogenesis. Fifth, detailed information on recovery time was only available in some but not all of the studies. Finally, accurate estimation of resolution time of striatal lesions depended on the completeness of follow-ups which could not be achieved in some studies.

conclusions
In conclusion, in an attempt to comprehensively investigate "diabetic striatopathy" taking into account the use of different terms for the disorder in literature, the present study analyzed the manifestations, course and treatments as well as possible pathogenesis of the disease. The results demonstrated that, although chorea could be successfully treated with glucose control only in one-fourth of the patients, the majority required additional anti-chorea medications for symptom control. Regarding imaging presentations, isolated putamen and combined putamen-caudate nucleus involvements were most common. Discrepancies between CT and MRI findings were noted in about one-sixth of the patients, whilst chorea and imaging anomalies did not appear concomitantly in around one-tenth of patients. Most cases showed resolution of imaging anomalies about three months on CT and over eight months on MRI. Haloperidol was most frequently used for chorea treatment which was successful in most cases. Moreover, pre-treatment intervals for chorea had no significant impact on patients' recovery time which was shorter for those with glucose control only (i.e., less than two weeks) than that for those requiring additional anti-chorea medications (i.e., one month). Furthermore, recurrence still occurred in close to one-fifth of documented patients even after resolution of striatal anomalies.