JNS-13896; No of Pages 2 Journal of the Neurological Sciences xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Paroxysmal kinesigenic dyskinesia in pseudohypoparathyroidism: Is basal ganglia calcification a necessary finding? Keywords: Paroxysmal kinesigenic dyskinesia Calcium Pseudohypoparathyroidism Calcification
range: 9–55 pg/ml]). In a thyroid function test, serum free T4 and TSH, thyroglobulin Ab, and microsomal Ab were within the normal range. In between attacks, we performed neurological and physical examinations as well as prolonged video-EEG monitoring with exercised provocation, which revealed non-specific findings. Upon these results, we diagnosed her as PKD associated with pseudohypoparathyroidism. She was treated with additional oral calcium replacement therapy, which resulted in the normalization of serum calcium levels and marked improvement of PKD episodes. Further genetic studies regarding the secondary pseudohypoparathyroidism as it may relate to ion channelopathy were not performed because of lack of patient consent.
Dear Editor, 2. Case 2 Paroxysmal dyskinesia is a rare neurological syndrome characterized by involuntary and intermittent movements with various combinations of these hyperkinetic disorders. Paroxysmal kinesigenic dyskinesia (PKD), one of the three main types of paroxysmal dyskinesia, is brief in its presentation ranging from seconds to 5 min and is precipitated by sudden attacks of dyskinesias induced by voluntary movements [1]. Since it is relatively uncommon, many PKD patients are misdiagnosed in clinical practice. Hypocalcemia, which resulted from either hypoparathyroidism or pseudohypoparathyroidism, is considered to be a rare cause of symptomatic PKD. It is also commonly associated with basal ganglia (BG) calcification. The patho-mechanisms underlying PKD and its association with calcium metabolism remain poorly understood [2]. Here, we report two clinical cases of PKD with pseudohypoparathyroidism-related hypocalcemia with and without BG calcification on brain imaging. 1. Case 1 A 27 year old woman was admitted following a brief seizure attack. A detailed history revealed that she had been exhibiting intermittent paroxysmal episodic involuntary movements since 16 years of age. She described stiffening of her legs and feet, while both her hands were flexed into a clawed position. Her right hemibody was more frequently affected. She remained conscious during each distinct attack. The duration of these episodes ranged from 5 to 10 s, with a frequency up to 5 times per day. Sudden movements, such as physical exercise typically preceded the attacks. During an episode, she was unable to stand or be mobile. She would sometimes fall down, but denied experiencing any auras, rhythmic twitching, tongue-biting, urination and postictal confusion upon attack. She stated that none of her close relatives exhibited the same symptoms. Her electroencephalogram (EEG) revealed occasional spikes in both temporal areas. Brain computed tomography (CT) revealed bilateral calcification in the basal ganglia (BG) (Fig. 1-A). Serologic studies were employed to differentiate calcified brain structures and revealed decreased levels of serum total calcium (4.4 mg/dL (normal range: 8.6–10.0 mg/dl)), and increased levels of inorganic phosphorus (6.1 mg/dl (normal range: 2.7–4.5 mg/dl)). Parathyroid hormone (PTH) levels were elevated (209.1 pg/ml [normal
A 25-year-old man was referred from a secondary hospital with a history of intermittent paroxysmal episodic involuntary movements. During his first attack, which was 5 years ago, he exhibited a head version to the right, along with his right arm being flexed. Episode duration was less than 5 s, and occurred approximately once a month. His symptoms became progressively worse, such that both upper and lower extremities became involved, and occurred with increasing frequency, up to 4 times a day. There was no pain or loss of consciousness during each distinct attack. Sudden movements, typically physical exercise, provoked the attacks. During an episode, he often fell down and dropped things from his hands, but did not exhibit any pre-ictal auras or rhythmic convulsive movement during these attacks. None of his family members exhibited similar symptoms. His initial provoked EEG was normal and routine brain CT had non-specific findings (e.g., no BG calcification) (Fig. 1-B). The patient had increased serum PTH levels of 266.4 pg/ml. In addition, serum total calcium, ionized calcium, and phosphorus levels were 5.3 mg/dl, 2.77 mmol/L, and 5.5 mg/dl respectively, which all were in abnormal level. Upon treatment with calcium, his serum calcium levels were still low, while PTH levels increased which was compatible to a diagnosis of pseudohypoparathyroidism. He was treated with additional oral calcium replacement therapy only, and the symptoms of his PKD episode completely disappeared. 3. Conclusion We discussed 2 case studies with pseudohypoparathyroidism, which was attributed to PKD: one with BG calcification, and one without BG calcification, as detected by brain CT. The first patient was initially admitted due to a sudden seizure attack, with a previous history of presumed PKD. Over the past several years, there has been debate as to whether PKD is an epileptic disorder or not. This is because of the brief, paroxysmal and stereotyped nature of PKD attacks and the dramatic improvement in response to anticonvulsants [2]. Although the presence of hypocalcemia in PKD patients may not be related to a genetic ion channel defect, the cases presented here suggest that serum calcium levels may play an important role in provoking
http://dx.doi.org/10.1016/j.jns.2015.06.067 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Y.-J. Kwon, et al., Paroxysmal kinesigenic dyskinesia in pseudohypoparathyroidism: Is basal ganglia calcification a necessary finding? J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.06.067
2
Letter to the Editor
Fig. 1. Brain computed tomography (CT) of a patient with (1-A) and without (1-B) bilateral basal ganglia calcification.
dyskinesias in idiopathic PKD. Any channelopathy affecting calcium metabolism may also have an important role with regard to PKD patho-mechanisms. For example, PKD patients respond favorably to several antiepileptic drugs, which can modulate ion channels located in neuronal cell membranes [3]. However, secondary PKD due to hypocalcemia should first be treated with systemic calcium replacement. In fact, both our patients were not treated with anticonvulsants, although anticonvulsants are typically used for management of PKD symptoms. Instead, the patients were supplied with daily calcium and vitamin D supplements, along with adjusted low-phosphate foods during every meal. Some previous reports regarding PKD have described the causal relationship between hypocalcemia [4] and BG calcification. Interestingly, some authors, moreover, compared the prevalences of BG calcification between idiopathic hypoparathyroidism and pseudohypoparathyroidism [5]. Although neuronal degeneration and gliosis surrounding BG calcium deposition are widely known pathologies associated with PKD [6], no pathogenic association has been established for the vulnerability of the BG regarding calcium deposits. Indeed, as seen in our second patient, BG calcification is not always a pathognomonic finding of secondary PKD. Some people might question that the presence of calcification would be related with the time interval for CT image from the first symptom onset. In fact, our two patients had different time intervals: Case 1 had ten years from her first symptom onset, whereas Case 2 had five years. According to Illum and Dupont, however, there is the lack of correlation between occurrence of calcification and length of case history [5]. Our report emphasizes two important concerns when treating PKD patients in clinical practice. First, physicians should consider chronic electrolyte imbalance as a possible, albeit rare, causal factor of PKD. It is easily detectable compared to complicated gene study, which is both costly and time consuming. Second, further investigation is warranted to examine the relationship between PKD and ion channelopathies. In fact, Fahr's
disease, a genetic form of ion channelopathy (sodium dependent phosphate transporter), is another possible cause of PKD. Currently, the BG calcification theory cannot fully explain the pathophysiology of PKD and its abnormal movements.
References [1] I. Unterberger, E. Trinka, Diagnosis and treatment of paroxysmal dyskinesias revisited, Ther. Adv. Neurol. Disord. 1 (2) (2008) 4–11. [2] C.T. Lombroso, Paroxysmal choreoathetosis: an epileptic or non-epileptic disorder? Ital. J. Neurol. Sci. 16 (5) (1995) 271–277. [3] V. Chen, Channelopathy linked to epilepsy and paroxysmal dyskinesia, Lancet Neurol. 4 (8) (2005) 462. [4] G. Barabas, S.M. Tucker, Idiopathic hypoparathyroidism and paroxysmal dystonic choreoathetosis, Ann. Neurol. 24 (4) (1988) 585. [5] F. Illum, E. Dupont, Prevalences of CT-detected calcification in the basal ganglia in idiopathic hypoparathyroidism and pseudohypoparathyroidism, Neuroradiology 27 (1) (1985) 32–37. [6] E.J. Chung, G.N. Cho, S.J. Kim, A case of paroxysmal kinesigenic dyskinesia in idiopathic bilateral striopallidodentate calcinosis, Seizure 21 (10) (2012) 802–804.
Ye-Ji Kwon Jin-Man Jung Jeong-Yoon Choi Do-Young Kwon⁎ Department of Neurology, Korea University Medical Center, Ansan Hospital, Ansan-city, Republic of Korea ⁎Corresponding author at: Department of Neurology, Korea University Medical Center, Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-city 425-707, Republic of Korea. Tel.: +82 31 412 5150. E-mail address: [email protected]. 17 May 2015 Available online xxxx
Please cite this article as: Y.-J. Kwon, et al., Paroxysmal kinesigenic dyskinesia in pseudohypoparathyroidism: Is basal ganglia calcification a necessary finding? J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.06.067
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Paroxysmal kinesigenic dyskinesia in pseudohypoparathyroidism: Is basal ganglia calcification a necessary finding? Keywords: Paroxysmal kinesigenic dyskinesia Calcium Pseudohypoparathyroidism Calcification
range: 9–55 pg/ml]). In a thyroid function test, serum free T4 and TSH, thyroglobulin Ab, and microsomal Ab were within the normal range. In between attacks, we performed neurological and physical examinations as well as prolonged video-EEG monitoring with exercised provocation, which revealed non-specific findings. Upon these results, we diagnosed her as PKD associated with pseudohypoparathyroidism. She was treated with additional oral calcium replacement therapy, which resulted in the normalization of serum calcium levels and marked improvement of PKD episodes. Further genetic studies regarding the secondary pseudohypoparathyroidism as it may relate to ion channelopathy were not performed because of lack of patient consent.
Dear Editor, 2. Case 2 Paroxysmal dyskinesia is a rare neurological syndrome characterized by involuntary and intermittent movements with various combinations of these hyperkinetic disorders. Paroxysmal kinesigenic dyskinesia (PKD), one of the three main types of paroxysmal dyskinesia, is brief in its presentation ranging from seconds to 5 min and is precipitated by sudden attacks of dyskinesias induced by voluntary movements [1]. Since it is relatively uncommon, many PKD patients are misdiagnosed in clinical practice. Hypocalcemia, which resulted from either hypoparathyroidism or pseudohypoparathyroidism, is considered to be a rare cause of symptomatic PKD. It is also commonly associated with basal ganglia (BG) calcification. The patho-mechanisms underlying PKD and its association with calcium metabolism remain poorly understood [2]. Here, we report two clinical cases of PKD with pseudohypoparathyroidism-related hypocalcemia with and without BG calcification on brain imaging. 1. Case 1 A 27 year old woman was admitted following a brief seizure attack. A detailed history revealed that she had been exhibiting intermittent paroxysmal episodic involuntary movements since 16 years of age. She described stiffening of her legs and feet, while both her hands were flexed into a clawed position. Her right hemibody was more frequently affected. She remained conscious during each distinct attack. The duration of these episodes ranged from 5 to 10 s, with a frequency up to 5 times per day. Sudden movements, such as physical exercise typically preceded the attacks. During an episode, she was unable to stand or be mobile. She would sometimes fall down, but denied experiencing any auras, rhythmic twitching, tongue-biting, urination and postictal confusion upon attack. She stated that none of her close relatives exhibited the same symptoms. Her electroencephalogram (EEG) revealed occasional spikes in both temporal areas. Brain computed tomography (CT) revealed bilateral calcification in the basal ganglia (BG) (Fig. 1-A). Serologic studies were employed to differentiate calcified brain structures and revealed decreased levels of serum total calcium (4.4 mg/dL (normal range: 8.6–10.0 mg/dl)), and increased levels of inorganic phosphorus (6.1 mg/dl (normal range: 2.7–4.5 mg/dl)). Parathyroid hormone (PTH) levels were elevated (209.1 pg/ml [normal
A 25-year-old man was referred from a secondary hospital with a history of intermittent paroxysmal episodic involuntary movements. During his first attack, which was 5 years ago, he exhibited a head version to the right, along with his right arm being flexed. Episode duration was less than 5 s, and occurred approximately once a month. His symptoms became progressively worse, such that both upper and lower extremities became involved, and occurred with increasing frequency, up to 4 times a day. There was no pain or loss of consciousness during each distinct attack. Sudden movements, typically physical exercise, provoked the attacks. During an episode, he often fell down and dropped things from his hands, but did not exhibit any pre-ictal auras or rhythmic convulsive movement during these attacks. None of his family members exhibited similar symptoms. His initial provoked EEG was normal and routine brain CT had non-specific findings (e.g., no BG calcification) (Fig. 1-B). The patient had increased serum PTH levels of 266.4 pg/ml. In addition, serum total calcium, ionized calcium, and phosphorus levels were 5.3 mg/dl, 2.77 mmol/L, and 5.5 mg/dl respectively, which all were in abnormal level. Upon treatment with calcium, his serum calcium levels were still low, while PTH levels increased which was compatible to a diagnosis of pseudohypoparathyroidism. He was treated with additional oral calcium replacement therapy only, and the symptoms of his PKD episode completely disappeared. 3. Conclusion We discussed 2 case studies with pseudohypoparathyroidism, which was attributed to PKD: one with BG calcification, and one without BG calcification, as detected by brain CT. The first patient was initially admitted due to a sudden seizure attack, with a previous history of presumed PKD. Over the past several years, there has been debate as to whether PKD is an epileptic disorder or not. This is because of the brief, paroxysmal and stereotyped nature of PKD attacks and the dramatic improvement in response to anticonvulsants [2]. Although the presence of hypocalcemia in PKD patients may not be related to a genetic ion channel defect, the cases presented here suggest that serum calcium levels may play an important role in provoking
http://dx.doi.org/10.1016/j.jns.2015.06.067 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Y.-J. Kwon, et al., Paroxysmal kinesigenic dyskinesia in pseudohypoparathyroidism: Is basal ganglia calcification a necessary finding? J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.06.067
2
Letter to the Editor
Fig. 1. Brain computed tomography (CT) of a patient with (1-A) and without (1-B) bilateral basal ganglia calcification.
dyskinesias in idiopathic PKD. Any channelopathy affecting calcium metabolism may also have an important role with regard to PKD patho-mechanisms. For example, PKD patients respond favorably to several antiepileptic drugs, which can modulate ion channels located in neuronal cell membranes [3]. However, secondary PKD due to hypocalcemia should first be treated with systemic calcium replacement. In fact, both our patients were not treated with anticonvulsants, although anticonvulsants are typically used for management of PKD symptoms. Instead, the patients were supplied with daily calcium and vitamin D supplements, along with adjusted low-phosphate foods during every meal. Some previous reports regarding PKD have described the causal relationship between hypocalcemia [4] and BG calcification. Interestingly, some authors, moreover, compared the prevalences of BG calcification between idiopathic hypoparathyroidism and pseudohypoparathyroidism [5]. Although neuronal degeneration and gliosis surrounding BG calcium deposition are widely known pathologies associated with PKD [6], no pathogenic association has been established for the vulnerability of the BG regarding calcium deposits. Indeed, as seen in our second patient, BG calcification is not always a pathognomonic finding of secondary PKD. Some people might question that the presence of calcification would be related with the time interval for CT image from the first symptom onset. In fact, our two patients had different time intervals: Case 1 had ten years from her first symptom onset, whereas Case 2 had five years. According to Illum and Dupont, however, there is the lack of correlation between occurrence of calcification and length of case history [5]. Our report emphasizes two important concerns when treating PKD patients in clinical practice. First, physicians should consider chronic electrolyte imbalance as a possible, albeit rare, causal factor of PKD. It is easily detectable compared to complicated gene study, which is both costly and time consuming. Second, further investigation is warranted to examine the relationship between PKD and ion channelopathies. In fact, Fahr's
disease, a genetic form of ion channelopathy (sodium dependent phosphate transporter), is another possible cause of PKD. Currently, the BG calcification theory cannot fully explain the pathophysiology of PKD and its abnormal movements.
References [1] I. Unterberger, E. Trinka, Diagnosis and treatment of paroxysmal dyskinesias revisited, Ther. Adv. Neurol. Disord. 1 (2) (2008) 4–11. [2] C.T. Lombroso, Paroxysmal choreoathetosis: an epileptic or non-epileptic disorder? Ital. J. Neurol. Sci. 16 (5) (1995) 271–277. [3] V. Chen, Channelopathy linked to epilepsy and paroxysmal dyskinesia, Lancet Neurol. 4 (8) (2005) 462. [4] G. Barabas, S.M. Tucker, Idiopathic hypoparathyroidism and paroxysmal dystonic choreoathetosis, Ann. Neurol. 24 (4) (1988) 585. [5] F. Illum, E. Dupont, Prevalences of CT-detected calcification in the basal ganglia in idiopathic hypoparathyroidism and pseudohypoparathyroidism, Neuroradiology 27 (1) (1985) 32–37. [6] E.J. Chung, G.N. Cho, S.J. Kim, A case of paroxysmal kinesigenic dyskinesia in idiopathic bilateral striopallidodentate calcinosis, Seizure 21 (10) (2012) 802–804.
Ye-Ji Kwon Jin-Man Jung Jeong-Yoon Choi Do-Young Kwon⁎ Department of Neurology, Korea University Medical Center, Ansan Hospital, Ansan-city, Republic of Korea ⁎Corresponding author at: Department of Neurology, Korea University Medical Center, Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-city 425-707, Republic of Korea. Tel.: +82 31 412 5150. E-mail address: [email protected]. 17 May 2015 Available online xxxx
Please cite this article as: Y.-J. Kwon, et al., Paroxysmal kinesigenic dyskinesia in pseudohypoparathyroidism: Is basal ganglia calcification a necessary finding? J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.06.067
