Diabetic striatopathy in type 1 diabetes mellitus: a rare conundrum

Abstract

Diabetic striatopathy is a clinicoradiological syndrome characterised by acute hyperkinetic movement disorder in the form of hemichorea-hemiballism with basal ganglia abnormalities in neuroimaging. The hallmark basal ganglia abnormalities appear as hyperdensities in CT brain and hyperintensities in MRI brain, which could mislead the clinician towards an erroneous diagnosis of cerebral haemorrhage. It is classically described in elderly patients with type 2 diabetes mellitus, and its occurrence in type 1 diabetes is extremely rare. This case report entails the clinical details of a young man in his 20s with type 1 diabetes mellitus who had uncontrolled blood glucose levels and presented with a recent onset of abnormal movements in his left upper and lower limbs. The semiology, biochemistry and radiological investigation findings and treatment are detailed. A clear understanding of the condition could lead to an early diagnosis, spare the patient unnecessary investigations and improve treatment outcomes.

Background

Acute severe hyperglycaemia can present with a spectrum of neurological manifestations ranging from mild disorientation to seizures, dyskinesias and coma. Diabetic striatopathy (DS) is a distinct clinicoradiological syndrome where the patient presents with unilateral dyskinesias in the form of chorea/ballism with characteristic basal ganglia abnormalities on neuroimaging. Typically described in elderly women with poorly controlled type 2 diabetes, it is extremely rare in type 1 diabetes with or without ketosis. Here, we describe a rare scenario where a young man with type 1 diabetes presented with unilateral choreiform movements owing to severe hyperglycaemia.

Case presentation

A young man in his 20s, diagnosed with type 1 diabetes mellitus 18 months ago following an episode of diabetic ketoacidosis was started on insulin therapy, which he defaulted 3 weeks ago. He presented to the endocrinology outpatient clinic with a 4-day history of continuous abnormal movements initially in the left upper limb and subsequently involving the left lower limb. It was not associated with fever/abdominal pain/vomiting/altered behaviour. No hypoglycaemic symptoms were reported. There was no medical history of rheumatic fever in the patient or neurological disorder in the family. The movements worsened during voluntary activities and were absent during sleep. On examination, he was conscious and cooperative with vital signs within normal limits. There was no tachycardia or tachypnoea. His left upper and lower limbs showed continuous, irregular movements of high frequency and low amplitude sparing face, indicative of hemichorea. There was no rigidity or bradykinesia. The assessment of muscle power was difficult owing to continuous choreiform movements. Rest of the neurological examination was normal. No Kayser-Fleischer rings, stigmata of chronic liver disease or skin lesions were identified on examination. His systemic examination was unremarkable.

Investigations

At admission, his plasma glucose level was 568 mg/dL, urine ketones were negative, and there was no acidosis in arterial blood gas analysis (pH: 7.39, HCO₃: 23 mEq/L) with a glycosylated haemoglobin level of 16.2%, suggesting poorly controlled diabetes mellitus without ketoacidosis. Serum osmolality was 314 mOsm/L, and serum electrolytes, renal and liver biochemistry, calcium profile and thyroid function tests were within normal limits. His investigations are listed in table 1. He also underwent CT and MRI of the brain, which are depicted in figure 1.

Table 1.

Biochemical investigations of the index patient

Investigation	Patient’s result	Reference range
Random blood glucose	568 mg/dL
pH	7.39	7.35–7.45
Serum bicarbonate	23 mEq/L	22–26 mEq/L
Serum osmolality	314 mOsm/L	280–290
Glycosylated haemoglobin	16.2%	<6.5%
Urine acetone	Negative	Negative
Haemoglobin	14.6 gm/dl	13–16 gm/dl
Total count	8300 cells/mm3	4000–10 000 cells/mm3
Serum creatinine	0.9 mg/dL	0.6–1.2 mg/dL
Serum sodium	137 mEq/L	135–145 mEq/L
Serum calcium	9.3 mg/dL	8.5–10.4 mg/dL
Serum phosphorous	4.1 mg/dL	2.5–4.5 mg/dL
Thyroid Stimulating Hormone (TSH)	1.7 mIU/ml	0.5–4.5 mIU/L
Total T4	7.9 mcg/dl	5–11 mcg/dl
Serum ceruloplasmin	36 mg/dL	> 20 mg/dL

Figure 1.

(A) CT brain showing hyperdensities in right caudate and lentiform nucleus (red arrow). (B) MRI brain T1-weighted sequence showing hyperintensities in right caudate (long arrow) and lentiform nucleus (short arrow). (C) T2 FLAIR sequence showing heterogenous hyperintensities in right caudate (long arrow) and lentiform nucleus (short arrow).

CT brain showed a hyperdense area involving the right caudate and lentiform nucleus (figure 1A), and MRI brain revealed T1 hyperintensities in the right caudate and lentiform nucleus with areas of blooming in the right globus pallidus on susceptibility-weighted imaging (SWI; figure 1B). The left striatal region was normal in morphology and signal.

Differential diagnosis

Serum ceruloplasmin and Anti Streptolysin-O (ASO) titres were normal. After ruling out the possible differential diagnosis of Sydenham’s chorea, Wilson’s disease and drug-induced dyskinesias, the diagnosis of DS was made.

Treatment

On admission, the patient was started on an insulin basal-bolus regimen (regular insulin with Neutral Protamine Hagedorn (NPH) insulin) with frequent monitoring of blood glucose. Despite atta ining good glycaemic control, dyskinetic movements persisted, although there was a slight reduction in their frequency. The patient was started on haloperidol at a dose of 5 mg/day in divided doses and clonazepam at 0.5 mg two times per day, and there was an appreciable reduction in the frequency of movements by 4 days. There was a complete resolution of dyskinesia after 3 weeks of treatment, following which the drugs were tapered and stopped.

Outcome and follow-up

On the last follow-up visit, 4 months after the episode, the patient was asymptomatic with good glycaemic control and no recurrence of symptoms. Glycaemic control was maintained on the insulin basal-bolus regime.

Discussion

DS, also known as ‘hyperglycaemic non-ketotic hemichorea/hemiballism’ and diabetic hemichorea/hemiballism is a clinicoradiological syndrome characterised by dyskinesias with basal ganglia abnormalities in neuroimaging. The prevalence of DS is estimated to be around 1 in 100 000, but there is a gross underestimation as most of the treating doctors are unaware of this condition and it may be misdiagnosed as intracerebral haemorrhage. Clinically, a patient with DS presents with dyskinesias in the form of chorea/hemiballism, which can be either unilateral or bilateral depending on whether the corpus striatum is involved unilaterally or bilaterally. In unilateral dyskinesia, contralateral striatum is involved. Literature review shows that >95% of the cases occur in patients with type 2 Diabetes mellitus (DM), which highlights the rarity of our case.¹ Around 90% of the reported cases are from Asian ethnic groups. The reason for this ethnic predilection is not known. DS is an under-recognised complication of diabetes mellitus typically occurring in those with long-standing uncontrolled DM. DS is encountered much less commonly in patients with type 1 diabetes when compared with type 2 DM. Women are affected slightly more commonly than men (1.7:1). The occurrence of DS in the setting of both diabetic ketoacidosis and hyperosmolar hyperglycaemic states has been reported previously.² Our patient did not satisfy the criteria for either. DS can occasionally be the presenting symptom of diabetes mellitus.

The caudate nucleus, putamen, globus pallidus and subthalamic nucleus have increased patients’ vulnerability for acute metabolic insults. During Hyperosmolar Hyperglycemic state (HHS), the cerebral Kreb’s cycle activity is suppressed and brain metabolism is shifted to alternative anaerobic pathways that use GABA, leading to its depletion. GABA deficiency causes disinhibition of the subthalamic nucleus and basal ganglia, resulting in dyskinetic movements. On the other hand, in ketosis, acetoacetate produced in the liver is channelled to GABA synthesis, avoiding its deficiency and thus explaining the reduced incidence of striatopathy in Diabetic Ketoacidosis (DKA). This could explain the reduced incidence in type 1 DM where hyperglycaemia often leads to ketosis. Though the GABA hypothesis could explain the symptoms of DS, the observed radiological features cannot be accounted for. Four different hypotheses have been postulated to explain the observed striatal imaging abnormalities, namely, petechial haemorrhages,³ mineral deposition (calcium/magnesium),⁴ destruction of myelin⁵ and gemistocyte accumulation following neuronal loss.⁶ Hyperglycaemia, hyperviscosity and diabetic vasculopathy causing regional blood-brain-barrier disruption also contribute to the pathogenesis of DS.⁷ Currently, several theories have been described to entail the pathogenesis of DS. Microvascular disease theory proposes the occurrence of small vessel changes including obliteration of vessel lumen, hyaline changes and neovascularisation akin to diabetic retinopathy. The occurrence of DS in subjects after respiratory and urinary tract infections and the identification of lymphocytic infiltration around the central nervous system (CNS) blood vessels and raised IgG in CSF has led to the proposal of ‘infection and autoinflammatory response theory’. Ischaemic injury theory was proposed following evidence of hypoperfusion of the striatum identified by arterial spin labelling MRI in a few patients with DS.⁸ Myelin destruction and reactive astrocytosis with abundance of gemistocytes causes basal ganglia T1 hyperintensities on MRI, while the hyperdensities observed in CT scan could be attributed to petechial haemorrhages and/or mineral deposition⁹ (table 2). The appearance of lesion on T2-weighted images could be hyper-, iso-, hypo- or mixed intensities based on the MRI appearance at different time periods following haemorrhage. In diffusion-weighted imaging (DWI), the affected areas show diffusion restriction with low apparent diffusion coefficient (ADC). The accumulation of swollen astrocytes and the associated cytotoxic oedema in the basal ganglia are thought to be the reasons for diffusion restriction. Follow-up with DWI has shown increase in ADC values closely mirroring the normalisation of blood glucose and improvement of clinical symptoms.⁸ SWI may show blooming if extensive petechial haemorrhages are present. Isolated putamen and combined putamen-caudate nucleus affection are the common patterns of neuroimaging abnormalities. Around 15% of the subjects show discordance between the imaging studies. MRI has been found to be more sensitive in identifying subtle changes in the striatal region, and it should be performed in situations where the clinical setting suggests a diagnosis of DS but CT brain is normal. In a patient with demonstrable abnormalities in CT brain, performing an MRI in addition may not be warranted as there is little evidence to suggest its role as a predictor of outcome. Few cases have been reported in the literature devoid of any imaging finding. Pathological studies have revealed selective neuronal loss, reactive gliosis, petechial haemorrhages and prominent arteriolar changes with wall thickening and foamy macrophage invasion and perivascular lymphocytic infiltration.

Table 2.

Diabetic striatopathy: salient features on imaging and histopathology

Method	Finding
CT scan (CT)	Hyperdensities in region of basal ganglia
MRI scan (MRI)	T1 hyperintensities of affected striatum is the most consistent finding Lesions may appear hyper-, hypo- or isointense on T2/FLAIR sequences Diffusion-weighted imaging shows diffusion restriction with low apparent diffusion coefficient Blooming artefacts may be seen on susceptibility-weighted images in case of extensive petechial haemorrhages
MR spectroscopy	In the affected striatum, decreased N-acetyl Aspartate (NAA)/creatinine ratio, normal choline/creatinine ratio, presence of myoinositol peak are observed. Contralateral striatum shows decreased NAA/creatinine ratio, increased choline/creatinine ratio and absence of myoinositol peak
Fluorodeoxyglucose (FDG) PET	Decreased uptake in the affected striatum
Single photon emission CT	Hypoperfusion in the affected striatal region
Histopathology	Arterial wall thickening with hyaline degeneration, capillary proliferation, infiltration of lymphocyte and macrophages

Putamen is the most common site of involvement followed by the caudate nucleus.¹ Increased sensitivity of dopaminergic receptors in the striatum due to oestrogen deficiency explains the higher incidence of DS in postmenopausal women. Chorea involves unilateral limbs with upper limb predilection though bilateral presentation is reported in 9.7% of subjects.¹ The pattern of clinical presentation may not always correlate with the radiological features as unilateral dyskinetic movements may be associated with bilateral basal ganglia changes on imaging.

Other conditions with an increased T1 signal in the basal ganglia region include Wilson disease and a striatocapsular infarct. Clinical conditions, which may present as striatal hyperdensity on CT brain, include hypertensive haemorrhages, basal ganglia calcifications, genetic diseases (tuberous sclerosis, Tay-Sachs disease, neurofibromatosis), toxic exposure (CO and manganese toxicity) and brain ischaemia (lenticulostriate infarction, postcardiac arrest). The striatocapsular infarct can be differentiated from DS by high signal of DWI with restriction on ADC. Internal capsule is characteristically spared in DS, unlike striatal haemorrhage. Wilson’s disease is differentiated by hyperintensity on T2-weighted imaging of basal ganglia and thalamus.

The mainstay of treatment in DS is the achievement and maintenance of good glycaemic control with correction of electrolyte abnormalities. Earlier case series had shown resolution of symptoms in around 70% of the subjects with glycaemic control alone. However, a recent analysis of previously published reports has shown that control of blood glucose alone could reverse dyskinesias in only one-fourth of the patients with the remaining requiring additional antichorea medications.¹ Dopamine receptor blockers (haloperidol/risperidone), dopamine depleting drugs (tetrabenazine) SSRIs and GABAergic drugs (clonazepam/gabapentin) have been tried. Time to resolution of symptoms was reported to be variable, ranging from 2 to 28 days.¹⁰ Those who had symptom reversal with glycaemic control alone would experience improvement in the first 48–72 hours itself. So, it may be advisable to wait for 2–3 days before initiating antichorea treatment. Dopamine receptor blockers should be started at low doses initially and slowly uptitrated based on clinical response as the use of high doses at the onset can increase the risk of acute dystonia and other extrapyramidal side effects.

No specific correlation has been observed between time to resolution and the blood glucose and serum osmolality at presentation or duration of diabetes although poor glycaemic control and advanced age at presentation have been linked with non-resolution/delayed resolution.¹⁰ The radiological abnormality may persist even after resolution of dyskinetic movements in a subset of patients. There is a possibility of recurrence of DS as described in a case report, where a woman in her 60’s had a relapse of hemiballismus during normoglycaemia. It was accompanied by waxing and waning T1 hyperintensities in the striatal region on MRI.²

Patient’s perspective.

The abnormal movements in my limbs were quite embarrassing to start with and were worsening day after day. The initial advice I got from a doctor nearby was that it could be a serious issue with the brain. I was quite relieved later to realise that it was a complication of high sugar levels in the brain and could be readily treated. This was a turning point in my life, and I made a vow to never stop my diabetes treatment on my own without my doctor’s advice.

Learning points.

• Diabetic striatopathy is a rare entity in type 1 diabetes mellitus.

• It should be a prime consideration in any diabetic patient presenting with acute-onset unilateral/bilateral choreoballismic movements.

• Awareness about this clinical entity will help clinicians to obtain early diagnosis and thus avoid unnecessary investigations and treatment.

• Early recognition by neuroimaging followed by strict glycaemic control and institution of antichorea medications leads to complete resolution in most cases.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).