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Although a myriad of neurological complications resulting from chronic micro- and macroangiopathy and acute metabolic perturbations in diabetes mellitus (DM) had been well documented, structured studies on acute-onset movement disorders among patients with DM were surprisingly left out until recently (,). Movement disorders can manifest either as the first manifestation of undiagnosed DM or in later advanced stages of the disease (-). Genesis of these abnormal movements can directly be attributed to hyperglycemia or hypoglycemia, and may result from diabetic complications such as vasculopathy and neuropathy (,). Moreover, there are syndromes or conditions which can present as movement disorders alongside DM (,). Aggressive glycemic control is known to alleviate abnormal movements in most of the cases (,,). Among all the movement semiologies discussed in literature, hemichorea-hemiballism is most frequently reported (,). Diabetic striatopathy (DS) is an umbrella term referring to a hyperglycemic condition associated with both or either one of the two following conditions: () acute onset chorea-ballism; () striatal hyperdensity on computed tomography (CT) or striatal hyperintensity on T1-weighted magnetic resonance imaging (MRI) (,,). We herein briefly summarize the movement disorders in DM keeping DS at the center of discussion. Epidemiological and clinical spectrum, pathophysiology, neuroradiological conundrums, and available treatment are discussed. We also have tried to shed light upon the knowledge gaps in understanding of this particular disease that need to be addressed.

At present there is no prospective epidemiological study to assess the incidence or prevalence data available regarding movement disorders in diabetes. Few retrospective analyses with weak study methodology showed the prevalence of DS was in order of 1% or even less (-). On the other hand, a prospective study by Dubey et al revealed that 17.4% patients were diabetic among 552 patients presented with acute onset movement disorders and its mimics (including epilepsia partialis continua in a movement disorder clinic (). A systematic review of 176 patients observed that the lion share of DS cases was reported from Asian countries (). Multiple factors like easy accessibility to healthcare, poor compliance to drugs, ethnicity, or genetic susceptibility might play roles, but it definitely requires more exploration. However, a study by Shafran et al revealed that DS was actually underdiagnosed in western populations leading to its underreporting ().

Acute onset movement disorders in diabetes had been reported in a wide range of age groups ranging from first to ninth decade (). The mean age of the patients was generally sixth to seventh decade observed in different case series or systematic reviews (,-). Two studies from India reported a relatively younger mean age (fifth decade) of presentation (,). Chen et al analyzing only the cases of hemichorea-hemiballism with ketotic hyperglycemia also found a median age of 54 years (). Across different studies over the years, notably, a woman preponderance (nearly 2 times in most of the studies) of hyperglycemic hemichorea-hemiballism movements had been observed (,-). The exact reason for this female predominance or the role of biological sex on hyperglycemia-induced acute movement disorders needs further study. Some have postulated that increased dopaminergic receptor sensitivity secondary to estrogen deficiency in the striatum among postmenopausal women might make them susceptible to hyperkinetic movement disorders (,). In contrast with this global scenario, the authors’ largest clinical series from India revealed a slight male predominance (52.5%) which needs further confirmation by replication in other independent studies ().

Among different movement semiologies described among diabetics (table-1), hemichorea-hemiballism is the most common and classically described (-). Dubey et al () in their largest clinical series showed that non-choreic, non-ballistic movements were present among 30.5% of 59 cases. Therefore, an immediate capillary blood glucose (CBG) measurement in all patients with any sort of acute onset movement disorders is of pivotal importance before ordering other costly and time-consuming investigations. Bilateral clinical involvement was identified in 37.2% of all patients and was significantly more common in non-choreoballistic movement disorders than choreoballism (). In an analysis by Chua et al bilaterality was documented in 9.7% DS cases (), whereas bilaterality was even more frequently (19.5%) observed in the series described by Dubey et al (). The latter was the only study which systematically assessed both the hyperglycemia-associated choreoballism and non-choreoballistic movement disorders. It observed no statistically significant differences regarding demographic or clinical variables between these two types of movement disorders except bilaterality and delay in diagnosis (more frequent in non-choreoballism than choreoballism) ().

Many a times seizures can mimic hyperkinetic movement disorders or sometimes both may coexist (). Most commonly epilepsia partialis continua mimics a movement disorder. It is not conventionally categorized as a movement disorder; but is rather a type of simple focal motor status epilepticus with frequent repetitive muscle jerks, usually arrhythmic, that continues over prolonged periods. Moreover, the epilepsia partialis continua patients have electroencephalographic changes. The differentials to be considered are stroke, associated opposite hemispheric structural defect/s, and space-occupying lesions. Non-ketotic hyperglycemia is a well-known cause of reversible epilepsia partialis continua (,).

Movement disorders have been described in different types of DM, including type 1, type 2 and type 3c diabetes (,,). DS is generally a complication of long-standing DM with poorly controlled glycemic status flared up by an acute hyperglycemic surge in a non-ketotic milieu. In the cohort of Dubey et al the mean duration of DM was 9.8 years and movement disorders were the presenting manifestation of previously undiagnosed DM in three cases (5.1%) (). Patient-level meta-analysis of previously published cases has found a higher number (17%) of DS cases having previously undiagnosed DM (). This discrepancy could be due to lack of screening or publication bias. Nonetheless, it is recommended to measure blood glucose levels at presentation among all patients with acute onset movement disorders irrespective of their past glycemic status. Importantly, the majority of the patients with DS bears the stigmata of other chronic microvascular diabetic complications ().

From the various previously reported speculative pathophysiological basis of DS, Dubey et al () proposed "ominous octet" of pathogenesis of DS, which includes sequential occurrence of following factors: 1) gemistocytopathy, 2) petechial hemorrhage, 3) methemoglobin deposition, 4) mineral (calcium and magnesium) deposition, 5) cytotoxic edema, 6) myelinolysis, 7) gliosis, and 8) atrophy. The hyperglycemic state results in hyperosmolarity and hyperviscosity leading to reduced cerebral blood flow causing insult to the striatal astrocytes which are exquisitely sensitive to ischemia. These tumescent reactive astrocytes are known as gemistocytes, the most consistent finding gathered from limited number of biopsy studies ().

Interestingly enough, genesis of majority of hyperglycemic movement disorders occurs in the background of non-ketotic milieu (,). In non-ketotic hyperglycemia brain metabolism is shifted towards the alternative anaerobic pathway in Krebs cycle causing depletion in gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. This leads to attenuated inhibition of the subthalamus by the medial globus pallidus resulting in hyperkinetic movements. Conversely, GABA can be readily re-synthesized from acetoacetate, which is in abundance in the ketotic milieu (). Hence, in the latter state, hyperkinetic movements rarely occur unless some other sinister mechanisms (such as cerebrovascular insufficiency or ultrastructural changes in basal ganglia) are at play ().

Although the sensitivity of MRI was observed to be higher than CT scan to detect DS (95.3% vs. 78.9%), the need for CT can’t be obviated in cases of negative MRI scans. There is plenty of cases where mismatch (defined as the complete absence of anomaly in basal ganglia on one imaging modality, but not the other) and incompatibility (defined as the difference in locations of striatal anomalies between CT and MRI) exist (). Hyperdensity on CT or hyperintensity on T1-weighted MRI in contralateral (to the side of the abnormal movements) putamen surrounding edema or mass effect, along with hyperglycemia and hemichorea-hemiballism movements, is pathognomonic of DS (). Putamen is the most commonly involved striatal structure, whereas isolated caudate or globus pallidus or subthalamic nucleus involvement seem to be less frequent (,). A significant portion of cases shows concomitant affliction of all three striatal components (putamen, caudate, and globus pallidus) (). The reason behind putaminal vulnerability to hyperglycemia and how the same anatomical lesion causes such wide arrays of movement disorders remain elusive.

The pathological basis behind the striatal hyperintensity on T1-weighted MRI and hyperdensity on CT scan in these patients can be proved by histopathological evidence of petechial hemorrhages causing accumulation of methemoglobin (). Unfortunately, this theory of microhemorrhages behind T1 hyperintensity can’t be substantiated well on corresponding gradient-echo images. In contrast, accumulation of gemistocytes due to ischemic events and neuronal dysfunction may partially explain the striatal hyperintensity on T1-weighted MRI, but not hyperdensity on CT (,). Few DS cases have documented restricted diffusion in diffusion-weighted imaging sequence (). Advanced imaging modalities such as MR volumetry, spectroscopy, functional MRI, positron emission tomography (PET), single photon emission CT (SPECT), susceptibility weighted MR, perfusion imaging etc. although not routinely done in clinical practice for diagnosis of DS, might unveil its intricate pathophysiological basis (,).

Previous studies showed that in different case series patients with choreo-ballistic movements did not have suggestive neuroimaging findings in 5-45% cases (clinically isolated DS) (,-,). Study focusing on both choreo-ballistic and non-choreo-ballistic movements revealed that only 44% cases had changes in brain MRI (). This wide variability had been attributed to the varied use of MRI or CT and non-homogenous neuroradiological definition of DS applied among various studies (,,). Moreover, neuroradiological changes lag behind the clinical manifestations. Nevertheless, it underscores the importance of initiating management by recognizing this disease phenomenon on the basis of clinical symptomatology (presence of acute onset movement disorders with concurrent hyperglycemia) without waiting for neuroimaging (). On the contrary, 2% of patients may show radiological striatal lesions without any clinically manifested movement disorders (radiologically isolated DS) (,-). There are also plenty of reports of clinical-radiological discordance or inconsistency in DS (,,). Thus, striatopathy with clinically manifested movement disorders (symptomatic DS) can be subdivided into two groups, i.e., 1) concordant: bilateral involuntary movements with bilateral DS, or unilateral involuntary movements with contralateral DS (); and 2) discordant: bilateral involuntary movements with unilateral DS or unilateral involuntary movements with bilateral or ipsilateral DS (,-). This frequently observed clinical-radiological dissociation in DS is apparently contradictory with the classical concept of neurological localization of lesion-manifestation and requires further studies with newer neuroimaging modalities (,). Due to the controversial and ambiguous nature of the term "diabetic striatopathy" in literature (), we had previously proposed a three-subset classification () (figure- 1).

Intensive management of hyperglycemia with insulin remains the pivotal measure to treat movement disorders associated with hyperglycemia (,). Some authors have speculated worsening of involuntary movements on aggressive lowering of blood glucose (analogous to diabetic retinopathy) (-), but this needs clarification by further reports. According to past studies, from one-fourth to almost half of the patients recover with insulin therapy alone (,,,) with a higher recovery rate in ketotic hyperglycemia cases (). Additional therapies such as haloperidol, tetrabenazine, risperidone, tiapride (ballism and chorea), levodopa (parkinsonism), trihexyphenidyl, clonazepam (dystonia), pramipexole (restless leg syndrome), propranolol (tremor), carbamazepine (hemifacial spasm) etc. have been used with varying success rates (,). Whether the requirement of additional drugs may be attributed to late presentation or diagnostic delay needs further study (,,,). Surgical interventions such as pallidotomy, ventrolateral thalamotomy, transcranial magnetic stimulation, and globus pallidus internus deep brain stimulation had been tried for intractable symptoms (,-).

In the study by Dubey et al (), treatment of movement disorders was documented and followed up for at least three weeks. Patients who recovered fully from all involuntary movements within seven days were regarded as early responders, while the rest were taken as late responders. In that series the majority (47.5%) of the patients had early and complete resolution of symptoms, 28.8% responded late but had a complete reversal, while 23.7% cases recovered partially. Interestingly, in Chua et al’s analysis recovery was earlier among patients on glucose-therapy only (2 days) compared to those receiving additional anti-chorea medications (14 days), although median pre-treatment lag period was identical between those two groups (4 days) (). Overall, the previous literature showed that recovery rate varied from 76.4% to 100% (,-), which could be attributable to heterogeneity in the definition of recovery (clinical and/or neuroradiological) and duration of follow-up employed across different studies. During recovery, as expected, symptomatic improvement precedes abolition of neuroradiological stigmata. Minimum time period for radiological reversal noted in study by Chua et al were 10 days on CT and 60 days on MRI. On follow-up MRI scans progressive increase in striatal hyperintensity to reach its maximum limit was noted at around 90 days, whereas the mean periods of complete radiological reversal were around 60 and 180 days on CT and MRI, respectively. The median duration of discernible changes on CT and MRI were 24 and 120 days respectively (). However, it is not at all uncommon to come across cases demonstrating persisting striatal anomalies on follow-up neuroimaging for months irrespective of symptomatic recovery (,,). Currently there is paucity of studies which longitudinally evaluate the evolution of radiological changes over the course of disease process.

Despite having limited data regarding long-term follow-up, nearly 20% cases of DS clinically recurred even after initial resolution of striatal anomalies., which underscored the importance of periodic neuroradiological surveillance even after initial recovery. Recurrence rate did not differ across different treatment modalities (i.e., with or without additional use of anti-chorea medications) employed ().

Acute onset or de novo movement disorder is one of the important neurological complications of DM, most prevalent but not limited to Asian population. Unfortunately, it is still less well-recognized among physicians, diabetologists, and endocrinologists leading to its diagnostic delay and probably poorer prognosis. Although DS and other movement disorders are generally complications of poorly controlled long-standing type 2 diabetes in the non-ketotic hyperglycemia state among elderly, it may be the first presentation of diabetes. Hence, clinicians must be aware of this entity so that crucial time is not wasted and readily available glucose measurement are ordered when dealing with such patients irrespective of their past glycemic status. Exact pathophysiological mechanisms, genetic basis, radiological correlates, and the explanation for the seemingly discordant clinical-radiological picture in hyperglycemia-induced movement disorders remain elusive. Much work needs to be done to determine the optimal management and prognostic indicators of this emerging disease entity.