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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