Discussion
The pathophysiology of NHHH is still not yet completely understood. According to a recent metanalysis[11], the estimated prevalence of 1:100,000 is thought to be underestimated due to the lack of knowledge about this condition. There is a slight predominance in females (male to female ratio of 1:1.7) and Asia contributes to 71.6% of the reported cases followed by Europe (8.5%) and the Americas (4%)[11].
The chorea of NHHH has some pathognomonic characteristics. According to their type and severity, the abnormal involuntary movements can be classified from mild chorea to severe ballism. Ballismus is uncoordinated wild-flinging movements caused by contraction of the proximal limb muscles[12]. Chorea consists of more continuous and random motions restricted to the distal muscles[13]. The movements usually have an acute or subacute onset, can present with different severities, are most commonly unilateral, rarely bilateral, resolve with sleep and are progressive if not treated [8]. They are typically associated with contralateral imaging findings mainly striatal hyperintensity on T1-weighted MR images or high density on CT scans in the basal ganglia, most commonly involving the putamen[11]. Moreover, improvement of the imaging findings usually lags the resolution of symptoms.
Many mechanisms have been proposed to explain NHHH. The most widely accepted theory is that during states of non-ketotic hyperglycemia, the Kreb’s cycle is inactivated, and the brain shifts to the anaerobic pathway and uses GABA as an energy source which ultimately gets depleted. The depletion of GABA, acetylcholine and resulting metabolic acidosis produces basal ganglia dysfunction leading to chorea. Inversely, ketones in DKA are used as an energy source producing GABA as a metabolite, hence the rarity of NHHH in children where T1D is much more common than T2D. However, this hypothesis does not explain why the manifestations are usually unilateral and don’t resolve promptly after glycemic control. Other theories include basal ganglia ischemia, hemorrhage, ion deposition and increased dopamine secretion[14]. Interestingly, our patient did not have urine ketones throughout his initial admission for abnormal movements. He did however have urine ketones on follow-up when his symptoms had completely resolved.
NHHH tends to have a good prognosis. The abnormal movements are reversible and the mainstay of treatment is achieving adequate glycemic control. However, symptoms may persist for weeks despite normoglycemia necessitating the addition of a therapeutic agent. Most commonly used drugs are dopamine antagonists such as haloperidol and risperidone, anticonvulsants such as valproic acid and topiramate, or benzodiazepines such as diazepam and clonazepam[15]. Our patient’s symptoms persisted for few weeks despite improved glycemic control for which he required valproic acid that was titrated to control his symptoms. His symptoms eventually resolved after 6 weeks and valproic acid was stopped.
Conclusion :
NHHH is a rare complication of diabetes mellitus especially in children. It is important for clinicals to have a high index of suspicion for NHHH in a patient with choreiform movements and hyperglycemia because the mainstay of treatment is achieving glycemic control. More importantly, as more youth are diagnosed with T2D and other rare forms of diabetes, the diagnosis of NHHH is important to recognize.
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