Basal Ganglia Calcification with Tetanic Seizure Suggest Mitochondrial Disorder

Background

Basal ganglia calcification (BGC) is a rare sporadic or hereditary central nervous system (CNS) abnormality characterized by symmetric or asymmetric deposition of calcium in the basal ganglia, the dentate nuclei, or the centrum semiovale [1,2]. Occasionally, BGC has been reported as a CNS manifestation of a mitochondrial disorder (MID) (Table 1) [3,4]. BGC in MIDs may be due to involvement of the parathyroid gland, resulting in hypoparathyroidism and thus hypocalcemia, or due to dysfunction of the proximal tubular system (Fanconi syndrome) [5]. Isolated affection of the parathyroid gland or the kidney in MIDs is rare. Usually, the parathyroid gland or kidneys are affected in multisystem MIDs, as was observed in this patient case.

Case Report

The patient was a 65-year-old Gypsy female, height 160 cm, weight 85 kg, who was admitted to the intensive care unit (ICU) after developing severe headache followed by shivering, dyspnea, and a bluish face, being initially interpreted as tonic clonic seizure. The individual and family history for seizure, however, was negative. She received diazepam from the emergency doctor but did not require intubation in the ICU. Her previous individual history was complex and included polyneuropathy, restless-leg syndrome, retinopathy, non-insulin dependent diabetes, hyperlipidemia, osteoporosis with wedge-shaped vertebrum T8 and T9 and consecutive hyperkyphosis, cervicalgia, lumbalgia, struma nodosa requiring thyroidectomy with consecutive hypothyroidism, adipositas, resection of a vocal chord polyp, arterial hypertension, coronary heart disease, atheromatosis of the aorta, peripheral artery disease, chronic obstructive pulmonary disease with emphysema, steatosis hepatis, mild renal insufficiency, impingement syndrome, spondylarthrosis of the lumbar spine, and hysterectomy. Her family history was positive for breast cancer (sister).

Clinical neurologic examination revealed right-sided hypoacusis, sore neck muscles, asymmetric lid fissures, bilateral dysmetria, wasting of the thighs, and reduced tendon reflexes on the lower limbs. Blood tests revealed polyglobulia, hypocalcemia and hyperphosphatemia over years, increased HbA1c, hypertriglyceridemia, renal insufficiency, hyperuricemia, and vitamin-D deficiency (Table 1). Parathormone in the serum was two times normal and two times slightly reduced (Table 1). Calcitonin was normal. There was no diabetes insipidus or hypothyroidism. ECG showed sinus rhythm, occasional ventricular ectopic beats, and transient left bundle branch block. Cerebral CT showed extensive hyperdensities of the basal ganglia bilaterally and a small bleeding of the left parietal cortex (Figure 1), which was confirmed by cerebral MRI. The bleeding was suspected to have resulted from rupture of a cavernoma. Computed tomography angiography (CTA) did not reveal a vascular malformation that could explain the bleeding. There were no cerebellar calcifications. EEG did not show paroxysmal activity. After substitution of calcium, no further tetanic seizures occurred.

Discussion

This patient case is interesting for several reasons. First, the patient most likely suffered from a non-specific mitochondrial multiorgan disorder syndrome (MIMODS). The patient’s clinical indications for MID were the multisystem nature of the clinical presentation and the specific combination of abnormalities. She had diabetes, hyperlipidemia, osteoporosis, thyroid dysfunction, steatosis hepatis, mild renal insufficiency, and short stature. A further argument for a MID was that a long-standing electrolyte disturbance already existed prior to her thyroidectomy, and the BGC. Though she had a number of cardiovascular risk factors (smoking, arterial hypertension, diabetes, hyperlipidemia), which could explain atherosclerosis, it could also be attributed to a mitochondrial defect. The presence of a similar clinical profile as in this patient has been previously reported in MID patients [6–10]. Since a MID would explain all of the clinical manifestations in the presented case, this constellation further supported the presence of a MID. Unfortunately, the patient did not undergo further detailed investigations for a MID, which is why information about the presence of a biochemical abnormality or a genetic defect is lacking in this report.

Second, the patient presented with marked BGC, which has been previously reported as a phenotypic feature of a MID (Table 2). BGC is usually associated with disturbed calcium or phosphate metabolism due to hypoparathyroidism or Fanconi syndrome [11–14]. MIDs with BGC, however, do not always show an association with parathyroid dysfunction. Additionally, BGC may be associated with infectious, metabolic, or genetic disease [15]. However, the exact pathogenetic background of BGC remains elusive; however, T2-hyperintensities in the basal ganglia in these patients may reflect a focal, slowly progressive inflammatory or metabolic process [16]. In an autopsy study of a single patient with MELAS syndrome, BGC was attributable to calcifications in the small arteries of the globus pallidus [17]. Stimulation of glutamate receptors in rats has been shown to result in calcification of various brain areas including the basal ganglia [18]. Patients with BGC frequently present with movement disorders (such as Parkinson syndrome, choreoathetosis, or ataxia), psychiatric abnormalities (such as behavioral disturbances, mood disorders, dysexecutive syndrome, or psychosis), stroke-like episodes, epilepsy, or dementia [19–22]. The prevalence of BGC is unknown but the incidence of BGC has been reported as 0.3–1.2% [23,24]. Treatment of BGC is symptomatic and does not follow a standardized regimen [16].

Third, the initial event which led to hospitalization was most likely a tetanic seizure based upon hypocalcemia on admission, absence of a history for epilepsy, absence of clinical features of a recent seizure (normal CK, no tongue bite, secessus, or postictal muscle aching or confusion and reorientation), and a negative history for meningitis, trauma, or epilepsy in other family members. An argument in favor of an epileptic seizure is the minimal cortical bleeding. The initial clinical manifestation, however, was similar to that of a tetanic seizure, which manifests with fear, inner agitation, short-lived impaired consciousness, hypoesthesias, paresthesias, muscle cramps, carpopedal spasms, Chvostek sign, Lust sign, Trousseau sign, tongue phenomenon, laryngospasms, obstetrician’s hand, expiratory apnea, intestinal colics, or repetitive discharges on needle EMG. Hypocalcemia could be attributed to diabetes insipidus, Fanconi syndrome, hypoparathyroidism, or hypothyroidism, of which only diabetes insipidus is unlikely.

Conclusions

This case shows that BGC together with diabetes and other endocrine or metabolic abnormalities suggest MID and that MID patients without a history of epilepsy, but with hypocalcemia, are more likely to develop tetanic seizures than epileptic seizures.