Calcification Mimicking Manganese-Induced Increased Signal Intensities in T1-Weighted MR Images in a Patient Taking Herbal Medicine: Case Report

NeuroToxicology 24 (2003) 835–838

Calcification Mimicking Manganese-Induced Increased Signal Intensities in T1-Weighted MR Images in a Patient Taking Herbal Medicine: Case Report Joon-Ho Ahn2, Cheol-In Yoo1, Choong Ryeol Lee1, Ji Ho Lee1, Hun Lee1, Chang-Yoon Kim2, Ji Kang Park3, Tadashi Sakai4, Chung Sik Yoon5, Yangho Kim1,* 1

Department of Occupational and Environmental Medicine, Ulsan University Hospital, #290-3 Cheonha-Dong, Dong-Ku, Ulsan 682-060, South Korea 2 Department of Psychiatry, College of Medicine, University of Ulsan, Ulsan, South Korea 3 Department of Radiology, Ulsan University Hospital, Ulsan, South Korea 4 Occupational Poisoning Center, Tokyo Rosai Hospital, Japan 5 Department of Occupational Health, Catholic University of Daegu, Daegu, South Korea Received 7 February 2003; accepted 21 April 2003

Abstract Characteristic high signal intensities confined to the globus pallidus on T1-weighted magnetic resonance image (MRI) can be observed in manganese (Mn)-exposed workers, however, these high signals should be differentiated from those due to other causes such as fat, hemoglobin breakdown products, melanoma, neurofibromatosis, and calcification. A 39-yearold woman was admitted with mutism and involuntary movements which had developed the day before. She had ingested two packs of liquid herbal medicine containing 0.53 mg of Mn daily for 4 months prior to visiting our hospital. Her MRI showed high signals, confined mainly to the globus pallidus on T1-weighted images. Follow-up brain MRI at an interval of 11 months showed no interval change. Brain computed tomography (CT) at the time of the second MRI showed symmetric calcification on both globus pallidus. Blood levels of liver function tests, calcium, phosphorus, and parathyroid hormone were within normal ranges. The increased signals, which were first presumed to be induced by Mn, were concluded to be due to calcification based on the following reasons. First, follow-up brain MRI at an interval of 11 months did not show any interval change. Second, the ingested amount of 1.06 mg Mn daily for 4 months is even less than that added to mineral supplements for adults. Third, Mn-induced high signals in T1-weighted MRI do not show any abnormal findings in brain CT. The present case report suggests that brain CT should be performed to rule out symmetric calcification on basal ganglia in patients showing increased signals in T1-weighted MRI, but who do not have a significant exposure history to Mn. The present report also showed that the amount of 1.06 mg Mn daily ingested for 4 months did not cause the high signal in brain MRI. # 2003 Elsevier Inc. All rights reserved.

Keywords: Calcification; High signal intensities; CT; MR

INTRODUCTION The manganese ion (Mn2þ) has five unpaired electrons in the 3d orbit, which results in its large magnetic * Corresponding author. Tel.: þ82-52-250-7281; fax: þ82-52-250-7289. E-mail address: [email protected] (Y. Kim).

moment, causing the shortening of T1-relaxation time and an increase in signal intensity on T1-weighted magnetic resonance images (MRI). Because of the paramagnetic quality of Mn, a bilateral symmetrical increase in signal intensities, confined to the globus pallidus and midbrain, can be observed on T1-weighted MRI, but with no alteration on the T2-weighted image. Characteristic high signal intensities confined to the

0161-813X/$ – see front matter # 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0161-813X(03)00060-3

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globus pallidus can be observed on T1-weighted MRI in experimental Mn poisoning of the non-human primate (Newland et al., 1989) and in patients with Mn neurointoxication (Nelson et al., 1993). Furthermore, the characteristic high signals are also highly prevalent in asymptomatic Mn-exposed workers (Kim et al., 1999b). A similar MRI pattern has been observed in patients receiving total parenteral nutrition, presumably owing to excessive Mn intake (Mirowitz et al., 1991; Ejima et al., 1992), and in patients with liver failure (Hauser et al., 1994; Krieger et al., 1995), presumably because of their inability to clear Mn. These changes in MRI tend to disappear following withdrawal from the source of Mn accumulation, despite permanent neurological damage (Nelson et al., 1993; Kim et al., 1999a). However, the Mn-induced high signal intensities on T1weighted images should be differentiated from those due to other causes such as fat (Markesberry et al., 1984), hemoglobin breakdown products (Gomori et al., 1985), melanoma (Gomori et al., 1986), neurofibromatosis (Mirowitz et al., 1989), and calcification (Dell et al., 1988; Henkelman et al., 1991). Iron deposits cause the shortening of the T2-relaxation time more predominantly than that of T1-relaxation time resulting in low signal intensity in the T2-weighted image, which is a differentiating point from a Mn deposit. Melanoma, and neurofibromatosis can be differentiated from Mninduced signals by the site and symmetricity. However, calcification-induced increased signals often behaves as same as Mn-induced signals. Brain computed tomography (CT) is used to distinguish increased signals due to Mn and calcification from each other, especially in the settings where a patient has exposed to Mn. Thus, we report a case of calcification mimicking Mninduced high signals in a patient taking herbal medicine containing Mn.

CASE REPORT A 39-year-old woman was admitted with mutism and involuntary movements which had developed the day before. She was alert and cooperative, but could not speak. Her eyes were blinking, and her head was nodding at an interval of 10–30 s. Neurologic examination showed no focal neurologic deficits. She began to speak the next day, but she could not recall what she had done 2 days before. Laboratory tests such as glucose, urea nitrogen, calcium, liver function tests, and complete blood cell counts were within normal range: EEG showed theta to delta slowing on both hemispheres suggesting mild abnormalities.

Before this admission, she had experienced several psychotic episodes, and so had taken the antipsychotic drug, haloperidol, intermittently for more than 10 years. Four months before admission, she developed dyskinetic movement of jaw, tongue and hands, and tardive dyskinesia was suspected, so haloperidol was changed to clozapine. Dyskinetic movements disappeared 20 days after the medication change. During admission, her symptoms were improved slowly and abnormal movements disappeared 4 days after the symptoms occurred. Similar symptoms recurred suddenly 2 months later and the symptoms disappeared the next day. She had ingested two packs of liquid herbal medicine daily for 4 months prior to visiting our hospital. Heavy metal concentrations in the liquid such as Mn, cadmium, chromium, arsenic, zinc, and copper were determined by a flameless graphite furnace atomic absorption spectrophotometry (AAS; Spectra AA880-GTA 100, Varian, Australia) (Baldwin et al., 1994; Francois et al., 1988). By the analysis of the liquid medicine, 100 ml of one pack contained 0.53 mg of manganese, 0.49 mg of cadmium, 8.3 mg of chromium, 7.1 mg of arsenic, 363.5 mg of zinc, 20.3 mg of copper, and an undetectable amount of lead. Her blood Mn concentration was 1.6 mg/dl, within the upper normal range. MRI studies of the brain were performed on a 1.5 T system (Signa Horizon LX; GE Medical Systems; Milwaukee, WI). Her MRI showed symmetrical increase in the signal intensities, confined mainly to the globus pallidus on T1-weighted images without corresponding abnormalities in T2weighted images (Fig. 1A and B). She had normal liver function. Follow-up brain MRI at an interval of 11 months showed no interval change (Fig. 2). Non-enhanced brain CT at the time of the second MRI showed symmetric calcification on both globus pallidus (Somatom plus 4; Siemens, Erlangen, Germany) (Fig. 3). Blood levels of calcium, phosphorus, and parathyroid hormone were within normal ranges. Family history of clinical disorders was not observed.

DISCUSSION The increased signals in T1-weighted MRI without corresponding alterations on the T2-weighted image, which were first presumed to be induced by Mn, were concluded to be due to calcification based on the following reasons. First, follow-up brain MRI at an interval of 11 months did not show any interval change. The Mninduced high signals in MRI usually disappear within 6 months or 1 year following the withdrawal from the

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Fig. 1. (A) Axial T1-weighted image (TR/TE, 466/14 ms) shows bilateral increased signal intensities at globus pallidus (filled arrows). (B) Axial T2-weighted image (TR/TE, 4000/100) shows no remarkable signal change at globus pallidus.

Fig. 2. Follow-up axial T1-weighted image (TR/TE, 466/14 ms) still shows no interval change of increased signal intensities at globus pallidus (filled arrows).

source of Mn accumulation (Newland et al., 1989; Nelson et al., 1993; Huang et al., 1998; Kim et al., 1999a). Second, the ingested amount of 1.06 mg Mn daily for 4 months is even less than that added to mineral supplements for adults. Many supplements contain up to 3 mg Mn per tablet (Andersen et al.,

Fig. 3. Axial non-enhanced CT (Kvp/mA, 120/240) scan shows bilateral calcification at globus pallidus (open arrows).

1999). Third, Mn-induced high signals in T1-weighted MRI do not show any abnormal findings in brain CT. Reports in the MRI literature have traditionally described the signal intensity of calcification as diminished or null effect (Holland et al., 1985; Oot et al., 1986; Tsuruda and Bradley, 1987; Atlas et al., 1988; Bangert et al., 1995). Recent studies have reported increased signal intensities of calcified brain tissue (Henkelman et al., 1991; Dell et al., 1988). Increased signal is only seen with low concentration of calcium, and the signal intensity progressively decreases as the calcium concentrations increase above 30–40% by weight (Henkelman et al., 1991). However, in all situations, the extent and degree of calcification are much clearer at brain CT (Norman et al., 1978; Atlas et al., 1988). Thus, brain CT is useful to diagnose the calcification rather than MRI. Symmetric calcification confined to both basal ganglia can be seen in idiopathic basal ganglia calcification (IBGC; Fahr’s Disease). IBGC is a rare disorder of unknown etiology that is manifested by neuropsychiatric abnormalities and abnormal involuntary movements. These symptoms may be subdivided into neurological (parkinsonism, dystonia, tremor, myoclonus, spasticity, epileptic seizures and coma) and cognitive disorders (amnesia and dementia); mood disorders (depression, mania, or bipolar disorders); and psychotic symptoms (auditory and visual hallucinations, paranoid delusions, ideas of reference, ideas of influence and catatonia) (Chabot et al., 2001). Also temporal lobe-like symptoms such as amnestic state, perceptual distortions, or complex visual hallucinations can occur (Lishman, 1978). The usual onset of the symptoms is in the fourth to sixth decade of the life (Manyam et al., 1992). Most cases are sporadic, although a few familial cases with autosomal dominant inheritance have been known. The condition is distinguished from other causes of

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basal ganglia calcification by normal calcium and phosphorus metabolism (Moskowitz et al., 1971). The present case had experienced schizophrenia-like symptoms such as visual hallucination and paranoid delusions before the amnestic state with involuntary movement developed, which symptom complex was compatible with those of IBGC. Thus, combined symmetric calcification confined to both basal ganglia in the present case was diagnosed as IBGC. However, the pathogenesis of IBGC is still unclear. The present case report suggests that brain CT should be performed to rule out symmetric calcification on basal ganglia in patients showing increased signals in T1-weighted MRI, but who do not have a significant exposure history to Mn. The present report also showed that the amount of 1.06 mg Mn daily ingested for 4 months did not cause the high signal in brain MRI.

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