Abstract

Nonketotic Hyperglycemic Chorea (NHC) is a rare neurological complication associated with uncontrolled diabetes mellitus, characterized by involuntary, irregular movements typically affecting one side of the body. This condition primarily affects elderly females of East Asian descent, with an estimated prevalence of less than 1 in 100,000 2, 3. Clinical presentation includes acute or subacute onset of hemichorea-hemiballismus and severe hyperglycemia without ketosis. This is a rare complication, and it is important to consider this as a differential in patients with hyperglycemia who present with movement disorders as it is potentially reversible with adequate blood sugar control. While most cases describe patients whose chief complaint was chorea-like symptoms, our patient's diagnosis was an incidental finding, further highlighting the importance of keeping this as a differential.

The pathophysiology involves a shift to anaerobic metabolism in the setting of hyperglycemia, depletion of gamma-aminobutyric acid (GABA) and acetate in the brain and subsequently decreased cerebral blood flow; which leads to basal ganglia dysfunction causing the choreiform movements.

We present a case of a patient who presented with new onset heart failure and was incidentally diagnosed with Nonketotic Hyperglycemic Chorea.

Case Description:

65-year-old woman with a PMH of T2DM and HTN presented to the ED with a 3–4-day history of SOB. She was found to be in Acute Renal Failure and had pulmonary edema and pleural effusions and subsequently received treatment with HD, diuretics and thoracentesis.

During the admission, the patient was noted to have mild involuntary spasms in her RLE, associated with poor coordination, including inability to perform heel shin test on the right leg. According to the patient’s daughter, she had been noticing involuntary jerking movements of the right leg intermittently which caused he significant disbalance over the past 1.5 months. Milder symptoms were also noted in the RUE. However, these were never worked up. These symptoms were affecting the patient’s quality of life as they interfered with her mobility.

An MRI of the brain showed nonspecific asymmetric T1 hyperintensity within the left basal ganglia and left caudate nucleus.  HbA1C done during the admission was 9.9. Her serum glucose ranged between the 150s to 300s, with the highest  being 301. The MRI findings in combination with hyperglycemia led us to diagnose this patient with non-ketotic hyperglycemic hemichorea.

Interestingly, the MRI also revealed small, acute infarcts in the left temporal and frontal periventricular white matter, likely related to uncontrolled hypertension. However, these findings did not correlate anatomically with the clinical symptoms of hemichorea seen in the patient.   Hyperglycemic non-ketotic hemichorea is best treated with VMAT 2 inhibitors like Deutrabenazine etc. As this medication was not available in the hospital formulary, inpatient management was focused on glycemic control with the patient to follow up outpatient with Neurology for possible treatment with VMAT 2 inhibitors.

Discussion:

This case highlights a rare but important cause of chorea: nonketotic hyperglycemic chorea (C-H-BG syndrome). This case illustrates an important presentation of NHC, where the primary complaint was not the typical choreiform movements, but rather an incidental finding of ataxia during hospital admission for new onset congestive heart failure (CHF). This highlights the importance of maintaining a high index of suspicion for NHC in patients with poorly controlled diabetes who present with any new-onset movement disorder or neurological symptoms.

The epidemiology of this entity reveals that it occurs predominantly in older females of Asian descent, and the HbA1c exceeded 10% in most patients. This is in line with our patient’s A1c of 9.9. However, most cases revealed higher average blood glucose levels whereas our patient mainly averaged in the 150s to 300. Some studies have also shown that NHC can exist without the characteristic imaging findings, suggesting that it is not a pre-requisite for diagnosis. Subsequently, NHC can be divided into two types; those with typical imaging findings and those without.

Prompt recognition is crucial, as NHC is potentially reversible with glycemic control, preventing unnecessary investigations and treatments, and minimizing potential morbidity. The pathophysiology of NHC remains incompletely understood, but several mechanisms have been proposed. The most invoked theory centers on metabolic disturbances within the basal ganglia induced by hyperglycemia. In the absence of sufficient insulin, cerebral metabolism shifts towards anaerobic pathways, leading to inactivation of the tricarboxylic acid cycle. This forces the brain to utilize gamma-aminobutyric acid (GABA) as an alternative energy source. In nonketotic states, unlike ketotic hyperglycemia where acetoacetate can be used to resynthesize GABA, GABA levels are rapidly depleted. The resultant reduction in GABA, a primary inhibitory neurotransmitter in the basal ganglia, disinhibits the thalamus, leading to hyperkinetic movements like chorea. Depletion of acetylcholine, also linked to the altered metabolic state, may further contribute to basal ganglia dysfunction.

Cerebrovascular insufficiency may also play a role. Poorly controlled diabetes increases the risk of cerebrovascular ischemia and reduces cerebral blood flow. It is plausible that the synergistic effects of vascular insufficiencies with uncontrolled non-ketotic hyperglycemia cause a transient dysfunction of the striatum and subsequent chorea. Some reports describe the finding of occlusive vasculopathy of the arterioles with patchy necrosis, neovascularization, and perivascular inflammation. A recent case reported striatal biopsy with findings similar to that seen in diabetic retinopathy, thus suggesting a local excitatory process within the striatum causing diabetic striatopathy.

The neuroimaging findings in our patient, specifically the asymmetric T1 hyperintensity in the left basal ganglia and caudate nucleus, are consistent with those described in other case reports of NHC. The characteristic neuroimaging findings in C-H-BG, specifically T1-weighted hyperintensity in the basal ganglia, particularly the putamen, are valuable diagnostic clues. While the exact etiology of these hyperintensities is debated; petechial hemorrhage, ischemia, or even calcification have been proposed. Pathological studies have demonstrated selective neuronal loss, gliosis, and reactive astrocytosis in the striatal areas. Importantly, follow-up imaging often demonstrates resolution or improvement of these findings with glycemic control, supporting the concept of a dynamic and reversible process. SPECT studies have demonstrated both initial hyperperfusion and subsequent hypoperfusion of the basal ganglia.

However, it's important to note that imaging findings can vary, and some patients may have normal imaging or other atypical findings. Some reports suggest T1 hyperintensity is more common in Asian populations, however as seen in our patient as well as published case series, other ethnicities may also present similarly. The presence of these findings, coupled with the patient's history of uncontrolled diabetes and clinical presentation, supported the diagnosis of NHC. It is also important to consider concomitant imaging findings unrelated to the current clinical presentation in nonketotic hyperglycemic chorea, such as underlying structural abnormalities, cerebrovascular accidents, etc. These are especially more common in aging patients with multiple comorbidities. Considering the overarching entity of uncontrolled diabetes and related atherosclerotic risk factors, this population is also amenable to cerebrovascular diseases including strokes which may be concomitantly present alongside other neurological entities.

Our patient’s ataxia was noted on Physical Therapy evaluation and subsequently the patient underwent MRI brain to rule out a possible stroke. The neurologist attributed the hemichorea to uncontrolled type 2 diabetes mellitus and the imaging findings of T2 hyperintensity in the left basal ganglia and caudate. While the patient did report rare involuntary movements of the right arm, the ataxia in her right leg was the more prominent symptom. The MRI did reveal an incidental stroke, however given the location and size, it was determined to be unrelated to her nonketotic hyperglycemic hemichorea. However, it is important to have a broad differential, as these hyperintense lesions may be seen in other diseases like chronic hepatic encephalopathy, post-cardiac arrest encephalopathy, hypoglycemic coma, and mild focal ischemia.

Management of NHC primarily involves strict glycemic control, which can often lead to the resolution of symptoms. In some cases, medications such as dopamine-depleting agents (e.g., tetrabenazine, valbenazine, deutetrabenazine – VMAT2 inhibitors) may be used to control the choreiform movements but are usually reserved for severe or persistent cases. In this case, treatment with VMAT2 inhibitors was recommended for outpatient management, as these medications were not available in the hospital formulary.

Conclusion

Nonketotic hyperglycemic chorea is a rare but treatable complication of uncontrolled diabetes. This case demonstrates that NHC can present with atypical symptoms (ataxia) and be discovered incidentally during evaluation for other medical conditions. Maintaining a high index of suspicion for NHC in patients with uncontrolled diabetes and new neurological symptoms is essential for prompt diagnosis and management. Further research is needed to better understand the epidemiology, pathophysiology, and optimal treatment strategies for this condition.