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Brain calcifications induce neurological dysfunction that can be reversed by a bone drug
Journal of the Neurological Sciences 243 (2006) 77 – 81 www.elsevier.com/locate/jns
Brain calcifications induce neurological dysfunction that can be reversed by a bone drug Jeffrey A. Loeb a,c,*, Sayyed A. Sohrab a, Mabubul Huq b, Darren R. Fuerst a a
Department of Neurology, Wayne State University School of Medicine, Detroit, MI, United States Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, United States The Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, United States b
c
Received 5 August 2005; received in revised form 23 November 2005; accepted 23 November 2005 Available online 23 January 2006
Abstract Perivascular calcifications within the brain form in response to a variety of insults. While considered by many to be benign, these calcium phosphate deposits or ‘‘brain stones’’ can become large and are associated with neurological symptoms that range from seizures to parkinsonian symptoms. Here we hypothesize that the high concentrations of calcium in these deposits produce reversible, toxic effects on neurons that can be overcome with ‘‘bone’’ drugs that chelate solid phase calcium phosphates. We present preliminary findings that suggest a direct association between progressive neurological symptoms and brain calcification and the symptomatic improvement of seizures, headaches, and parkinsonian symptoms in patients treated with the bisphosphonate drug disodium etidronate, normally used to treat bone diseases. Future, longitudinal epidemiological studies and randomized trials will be needed to determine the true relationship between brain stones and neurological disorders as well as the utility of bisphosphonates in their prevention and treatment. D 2005 Elsevier B.V. All rights reserved. Keywords: Calcification; Epilepsy; Headache; Bisphosphonate; Etidronate; Cavernous hemangioma; Neurocysticercosis
1. Introduction Intracerebral calcifications can form from various injuries (infection, ischemia, and trauma) [1]. They develop months to years following the injury, and range in size from large, macroscopic ‘‘brain stones’’ to microscopic perivascular accumulations [2]. They are best seen on brain CAT scans where they tend to concentrate in the basal ganglia in diseases such as Fahr’s Disease, but can also accumulate within the cerebral cortex, cerebellar nuclei and within tumors (Figs. 1, 3 and 4). A plausible mechanism by which these intraparenchymal calcifications form is shown in Fig. 2, where an injurious process to the brain leads to progressive, perivascular accumulations of calcium phosphate. Molecular anal-
* Corresponding author. Department of Neurology and Center for Molecular Medicine and Genetics, Elliman 3122, 421 E. Canfield Ave., Detroit, MI 48201, United States. Tel.: +1 313 577 9827; fax: +1 313 577 7552. E-mail address: [email protected] (J.A. Loeb). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.11.033
ysis shows they are composed predominantly of hydroxyapatite, the same calcium phosphate complex present in bone [3]. While the effect of these calcifications on neurons is not known, it is reasonable to suggest that high local calcium concentrations are generated producing deleterious effects. The high prevalence of neurological comorbidities, including seizures, headaches, and movement disorders, suggests a direct association. Consistently, patients with neurocysticercosis, perhaps the most common cause of epilepsy in the world, have a higher incidence of epilepsy in those with brain calcifications [4,5]. Here, we propose: (1) that brain calcifications produce neurological dysfunction that can lead to the development of seizures, headaches, and movement disorders, and (2) that calcium chelation using a bisphosphonate bone drug called disodium etidronate can improve these symptoms. We reported previously the effective use of this drug in the parkinsonian features of a patient with extensive basal ganglia calcifications due to Fahr’s Disease [6]. We now extend our observations to two additional patients with
78
J.A. Loeb et al. / Journal of the Neurological Sciences 243 (2006) 77 – 81
Fig. 1. Intracerebral calcfications in the human brain are readily seen by CAT scan. Two examples are shown of brain calcifications concentrated in the basal ganglia (two panels on left) and in the cerebral cortex (right panel and see Figs. 3 and 4).
brain lesions associated with cortical calcifications, who developed seizures and headaches concurrent to the formation of punctate calcifications. 2. Methods Our protocol was approved by the Wayne State University Human Investigation Committee and informed consent was obtained. Following over 6 months of baseline measurements, patients were treated in a double-blind manner with either 15 mg/kg disodium etidronate or placebo (A), divided twice daily for 6-months. During the subsequent 6 months (B), they were switched to the other treatment. At the end of 12 months, a follow up CAT scan was performed to compare calcifications to a baseline CAT scan. Blood tests for anticonvulsants, calcium, phosphorous were measured at onset, 6, and 12 months. Medication changes during the study included Patient 1 starting on acetazolamide for headaches 2 months before starting treatment A, and a reduction in oxcarbazepine from 1050 to 600 mg/day 2 weeks into treatment A because of side effects (blurred vision and somnolence). Patient 2 reduced her phenobarbital dose from 120 mg bid to 60 mg bid 2 months into treatment B. Headaches and seizures were measured as the number of days with symptoms per month. A sign test (a = 0.01) was used to determine if the data per period differed from zero.
year (Fig. 3, Year 1) he developed severe headaches and frequent ‘‘deja-vu’’ partial seizures up to about 2/day. MRIs showed a steady progression of the degree of calcification (seen as darkening) that started in the center of each lesion and continued to grow outward. This was confirmed by CAT scans (compare Years 1 to Years 2–4, Fig. 3 and CAT scans). The close correlation between the development of calcifications and headaches and seizures raises the possibility that
3. Patients 3.1. Patient 1 This boy presented at age 8 with acute myelogenous leukemia. He underwent chemotherapy followed by heterologous bone marrow transplantation after which he developed graft versus host disease that was further treated with steroids and FK-506. He developed ‘‘placidity’’ and short-term memory loss one month later. An MRI (Fig. 3, Year 0) showed T2 bright lesions in the left temporal and frontal lobes with no enhancement or mass effect. The etiology of these lesions was never determined. After one
Fig. 2. A model for the growth of perivascular calcifications at the site of brain injury that produce toxic effects on nearby neurons.
J.A. Loeb et al. / Journal of the Neurological Sciences 243 (2006) 77 – 81
79
treated empirically for toxoplasmosis and herpes encephalitis. Serology for toxoplasmosis and neurocysticercosis were negative. A lumbar puncture was normal except for a white cell count of 10. An MRI (Year 4, Fig. 2) showed perilesional edema in the left temporal lobe that subsequently resolved with seizure control and steroids [7]. Seizures, headaches, and frequent behavioral outbursts failed to respond to multiple anticonvulsant medications. 3.2. Patient 2 This 45 y/o woman was initially thought to have schizophrenia because of frequent episodes of confusion, agitation, and delusion that were later correlated with frequent ictal and post-ictal activities on long-term EEG monitoring. She had multiple seizure types. In one, she would become stiff, jerk all over, and mumble with eyes rolled back. In others, she would take a pen and jab herself or complain of intense pain for up to 20 min. Postictally, she would be confused, but amnestic for the seizure. Between seizures, she was often disoriented, confused, and inappropriate, and showed frequent epileptic activities on EEG monitoring in bilateral temporal regions. MRI and CAT scans (Fig. 4) showed a calcified cavernous hemangioma in
Fig. 3. Progressive calcification at two sites in Patient 1. Two focal areas of injury developed in an 8 y/o boy with graft versus host disease became calcified from the center of each lesion over the next few years. These T2-weighted MRI images (top panel) change from bright to dark as the lesions become more calcified. CAT scans shown in the bottom panels before and after disodium etidronate treatment did not change, but clearly show the calcifications as white areas.
these new, late-appearing symptoms were caused and/or exacerbated by the calcifications. One year later, his seizure frequency increased to 4/day and he developed inappropriate behaviors (seen as a peak in seizures and headaches in Fig. 5 months 6 – 9). He was
Fig. 4. Left occipital calcification at the site of a cavernous hemangioma in Patient 2. The MRI shows this as dark, while the unchanged CAT scans on the bottom panels show the calcifications as white.
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J.A. Loeb et al. / Journal of the Neurological Sciences 243 (2006) 77 – 81
the left occipital region. She failed to respond to a number of anti-epileptic medications including carbamazepine, gabapentin, phenytoin, and phenobarbital.
reduction in calcification size was detected for either patient.
5. Discussion 4. Results 5.1. A new disease and its treatment? Baseline seizure and headache frequencies were plotted as days/month with either seizures or headaches for each patient (Fig. 5). Compared to baseline levels, both patients had significant reductions in their symptoms (a = 0.01), including their inappropriate behaviors, after initiation of treatment A, which was disodium etidronate for both patients. These improvements had an initial lag of 2 –3 months, but appeared to be long-lasting even during the subsequent placebo treatment. Most remarkably, Patient 1 had a significant reduction of his headaches from 10.1 days/month at baseline to 4.5 days/month with disodium etidronate. Patient 2 had improved seizure control from 3.6 days/month at baseline to 2.0 days/month with treatment, a 45% reduction. Patient 1 also had a reduction in seizure frequency from 3.2 days/month at baseline to 2.1 days/month, a 34% reduction. Seizures and headaches were concomitant in Patient 1, suggesting a physiological relationship between the seizures and the headaches. As shown in the CAT scans in Figs. 3 and 4, no
Based on these two patients and previously published reports [5,6], we hypothesize that focal calcific deposits within the brain are not benign and lead to neurological dysfunction. Patient 1 developed progressive symptoms of seizures and headaches coincident with progressive calcification of focal cerebral lesions 1– 2 years following an unknown neurological illness. This patient also developed perilesional edema surrounding the larger of the calcified lesions in the setting of frequent partial seizures, suggesting a direct relationship between the calcified lesion and his seizures [7]. We also propose that neurological symptoms associated with brain calcifications can be reduced with the bone drug disodium editronate. Patient 1 had reduced seizure and headache frequencies and Patient 2 had reduced seizures with the bisphosphonate. While these are clearly early findings, disodium etidronate treatment was associated with a seizure reduction that exceeds many add-on anticonvulsant therapies (10 – 29%) [8,9], but does not produce the cognitive side effects seen with most anticonvulsants. Disodium etidronate treatment of a patient with Fahr’s Disease (left panel of Fig. 1), where calcifications are restricted mostly to the basal ganglia, showed a similar, delayed, but lasting improvement in parkinsonian symptoms [6]. Despite the large number of patients that have cerebral calcifications, there is little data from the literature on whether the calcifications themselves are harmful and warrant treatment. To date, the most extensively studied disease that has linked calcification to recurrent seizures is neurocysticercosis [5]. A recent study from India found that while not all patients develop recurrent seizures following initial brain infection, patients that later develop punctuate calcifications are more likely to develop recurrent seizures [4]. Another study using magnetization transfer MRI further refines this by suggesting that calcifications with surrounding gliosis are more likely to become epileptic [10]. On the other hand, a study from Brazil in patients with mesial temporal lobe sclerosis found no significant differences in cognitive performances in those with calcifications from neurocysticercosis and hippocampal sclerosis compared to those with hippocampal sclerosis alone [11]. 5.2. Calcium, neurons, and bisphosphonates
Fig. 5. Double-blind cross-over study with disodium etitronate. The number of days/month with seizures or headaches for Patient 1, and seizures for Patient 2, is shown before and during disodium etidronate (A), and placebo (B) treatments.
Previous studies have implicated calcium channels in the generation of seizure activity; however, calcium channel blockers have not been therapeutically effective in epilepsy
J.A. Loeb et al. / Journal of the Neurological Sciences 243 (2006) 77 – 81
as they have been for headaches [12]. High concentrations of calcium are also known to promote cell death through excitotoxic mechanisms [13]. Here we have postulated and provided some initial testing for the novel use of bisphosphonate drugs for brain calcifications because of their use for disease of bone and ectopic calcifications elsewhere in the body [14]. Disodium etidronate prevents calcium phosphate breakdown, inhibits the precipitation of calcium phosphate, blocks the transformation of amorphous calcium phosphate into hydroxyapatite, and delays aggregation of apatite crystals into larger clusters [14]. In the brain, bisphosphonates can reach brain calcifications through break down of the blood brain barrier [15]. There, the drug may bind calcifications with high affinity, protecting neurons from toxic calcium levels that promote excitability and death. 5.3. The next steps The natural history of brain calcifications are difficult to predict as are the development of related neurological symptoms. Prospective, longitudinal studies that directly relate neurological symptoms to the formation of macroscopic calcifications as well as large-scale clinical trails with bisphosphonates to both prevent and treat cerebral calcifications could be an effective approach to treat patients with brain stones. This may be of particular relevance in the infectious brain diseases such as neurocysticercosis, that commonly develop multiple calcific deposits often associated with life-long seizures.
Acknowledgments We thank Procter and Gamble Pharmaceuticals for providing the disodium etitronate and placebo for this study and for valuable discussions.
81
References [1] Davis RL, Robertson DM. Textbook of neuropathology. 2nd ed. Baltimore’ Williams and Wilkins; 1991 [ed.]. [2] Lowenthal A, Bruyn GW. Striopallidodentate calcification. Handb Clin Neurol 1968;6:712 – 6. [3] Smeyers-Verbeke J, Michotte Y, Pelsmaeckers J, Lowenthal A, Massart DL, Dekegel D, et al. The chemical composition of idiopathic nonarteriosclerotic cerebral calcifications. Neurology 1975; 25(1):48 – 57. [4] Thussu A, Arora A, Prabhakar S, Lal V, Sawhney IM. Acute symptomatic seizures due to single CT lesions: how long to treat with antiepileptic drugs? Neurol India 2002;50(2):141 – 4. [5] Nash TE, Del Brutto OH, Butman JA, Corona T, Delgado-Escueta A, Duron RM, et al. Calcific neurocysticercosis and epileptogenesis. Neurology 2004;62(11):1934 – 8. [6] Loeb JA. Functional improvement in a patient with cerebral calcinosis using a bisphosphonate. Mov Disord 1998;13(2):345 – 9. [7] Nash TE, Patronas NJ. Edema associated with calcified lesions in neurocysticercosis. Neurology 1999;53(4):777 – 81. [8] Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res 2001;47(1 – 2):17 – 25. [9] Deckers CL, Knoester PD, de Haan GJ, Keyser A, Renier WO, Hekster YA. Selection criteria for the clinical use of the newer antiepileptic drugs. CNS Drugs 2003;17(6):405 – 21. [10] Agarwal A, Raghav S, Husain M, Kumar R, Gupta RK. Epilepsy with focal cerebral calcification: role of magnetization transfer MR imaging. Neurol India 2004;52(2):197 – 9. [11] Terra-Bustamante VC, Coimbra ER, Rezek KO, Escorsi-Rosset SR, Guarnieri R, Dalmagro CL, et al. Cognitive performance of patients with mesial temporal lobe epilepsy and incidental calcified neurocysticercosis. J Neurol Neurosurg Psychiatry 2005;76(8):1080 – 3. [12] Chaisewikul R, Baillie N, Marson AG. Calcium antagonists as an addon therapy for drug-resistant epilepsy. Cochrane Database Syst Rev(4):CD002750. [13] Sattler R, Tymianski M. Molecular mechanisms of calcium-dependent excitotoxicity. J Mol Med 2000;78(1):3 – 13. [14] Fleisch H. Bisphosphonates: a new class of drugs in diseases of bone and calcium metabolism. Recent Results Cancer Res 1989;116:1 – 28. [15] Hui C, Lau KK. Intracranial Tc99m MDP uptake in Sturge – Weber syndrome. Australas Radiol 2003;47(1):75 – 7.
Brain calcifications induce neurological dysfunction that can be reversed by a bone drug Jeffrey A. Loeb a,c,*, Sayyed A. Sohrab a, Mabubul Huq b, Darren R. Fuerst a a
Department of Neurology, Wayne State University School of Medicine, Detroit, MI, United States Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, United States The Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, United States b
c
Received 5 August 2005; received in revised form 23 November 2005; accepted 23 November 2005 Available online 23 January 2006
Abstract Perivascular calcifications within the brain form in response to a variety of insults. While considered by many to be benign, these calcium phosphate deposits or ‘‘brain stones’’ can become large and are associated with neurological symptoms that range from seizures to parkinsonian symptoms. Here we hypothesize that the high concentrations of calcium in these deposits produce reversible, toxic effects on neurons that can be overcome with ‘‘bone’’ drugs that chelate solid phase calcium phosphates. We present preliminary findings that suggest a direct association between progressive neurological symptoms and brain calcification and the symptomatic improvement of seizures, headaches, and parkinsonian symptoms in patients treated with the bisphosphonate drug disodium etidronate, normally used to treat bone diseases. Future, longitudinal epidemiological studies and randomized trials will be needed to determine the true relationship between brain stones and neurological disorders as well as the utility of bisphosphonates in their prevention and treatment. D 2005 Elsevier B.V. All rights reserved. Keywords: Calcification; Epilepsy; Headache; Bisphosphonate; Etidronate; Cavernous hemangioma; Neurocysticercosis
1. Introduction Intracerebral calcifications can form from various injuries (infection, ischemia, and trauma) [1]. They develop months to years following the injury, and range in size from large, macroscopic ‘‘brain stones’’ to microscopic perivascular accumulations [2]. They are best seen on brain CAT scans where they tend to concentrate in the basal ganglia in diseases such as Fahr’s Disease, but can also accumulate within the cerebral cortex, cerebellar nuclei and within tumors (Figs. 1, 3 and 4). A plausible mechanism by which these intraparenchymal calcifications form is shown in Fig. 2, where an injurious process to the brain leads to progressive, perivascular accumulations of calcium phosphate. Molecular anal-
* Corresponding author. Department of Neurology and Center for Molecular Medicine and Genetics, Elliman 3122, 421 E. Canfield Ave., Detroit, MI 48201, United States. Tel.: +1 313 577 9827; fax: +1 313 577 7552. E-mail address: [email protected] (J.A. Loeb). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.11.033
ysis shows they are composed predominantly of hydroxyapatite, the same calcium phosphate complex present in bone [3]. While the effect of these calcifications on neurons is not known, it is reasonable to suggest that high local calcium concentrations are generated producing deleterious effects. The high prevalence of neurological comorbidities, including seizures, headaches, and movement disorders, suggests a direct association. Consistently, patients with neurocysticercosis, perhaps the most common cause of epilepsy in the world, have a higher incidence of epilepsy in those with brain calcifications [4,5]. Here, we propose: (1) that brain calcifications produce neurological dysfunction that can lead to the development of seizures, headaches, and movement disorders, and (2) that calcium chelation using a bisphosphonate bone drug called disodium etidronate can improve these symptoms. We reported previously the effective use of this drug in the parkinsonian features of a patient with extensive basal ganglia calcifications due to Fahr’s Disease [6]. We now extend our observations to two additional patients with
78
J.A. Loeb et al. / Journal of the Neurological Sciences 243 (2006) 77 – 81
Fig. 1. Intracerebral calcfications in the human brain are readily seen by CAT scan. Two examples are shown of brain calcifications concentrated in the basal ganglia (two panels on left) and in the cerebral cortex (right panel and see Figs. 3 and 4).
brain lesions associated with cortical calcifications, who developed seizures and headaches concurrent to the formation of punctate calcifications. 2. Methods Our protocol was approved by the Wayne State University Human Investigation Committee and informed consent was obtained. Following over 6 months of baseline measurements, patients were treated in a double-blind manner with either 15 mg/kg disodium etidronate or placebo (A), divided twice daily for 6-months. During the subsequent 6 months (B), they were switched to the other treatment. At the end of 12 months, a follow up CAT scan was performed to compare calcifications to a baseline CAT scan. Blood tests for anticonvulsants, calcium, phosphorous were measured at onset, 6, and 12 months. Medication changes during the study included Patient 1 starting on acetazolamide for headaches 2 months before starting treatment A, and a reduction in oxcarbazepine from 1050 to 600 mg/day 2 weeks into treatment A because of side effects (blurred vision and somnolence). Patient 2 reduced her phenobarbital dose from 120 mg bid to 60 mg bid 2 months into treatment B. Headaches and seizures were measured as the number of days with symptoms per month. A sign test (a = 0.01) was used to determine if the data per period differed from zero.
year (Fig. 3, Year 1) he developed severe headaches and frequent ‘‘deja-vu’’ partial seizures up to about 2/day. MRIs showed a steady progression of the degree of calcification (seen as darkening) that started in the center of each lesion and continued to grow outward. This was confirmed by CAT scans (compare Years 1 to Years 2–4, Fig. 3 and CAT scans). The close correlation between the development of calcifications and headaches and seizures raises the possibility that
3. Patients 3.1. Patient 1 This boy presented at age 8 with acute myelogenous leukemia. He underwent chemotherapy followed by heterologous bone marrow transplantation after which he developed graft versus host disease that was further treated with steroids and FK-506. He developed ‘‘placidity’’ and short-term memory loss one month later. An MRI (Fig. 3, Year 0) showed T2 bright lesions in the left temporal and frontal lobes with no enhancement or mass effect. The etiology of these lesions was never determined. After one
Fig. 2. A model for the growth of perivascular calcifications at the site of brain injury that produce toxic effects on nearby neurons.
J.A. Loeb et al. / Journal of the Neurological Sciences 243 (2006) 77 – 81
79
treated empirically for toxoplasmosis and herpes encephalitis. Serology for toxoplasmosis and neurocysticercosis were negative. A lumbar puncture was normal except for a white cell count of 10. An MRI (Year 4, Fig. 2) showed perilesional edema in the left temporal lobe that subsequently resolved with seizure control and steroids [7]. Seizures, headaches, and frequent behavioral outbursts failed to respond to multiple anticonvulsant medications. 3.2. Patient 2 This 45 y/o woman was initially thought to have schizophrenia because of frequent episodes of confusion, agitation, and delusion that were later correlated with frequent ictal and post-ictal activities on long-term EEG monitoring. She had multiple seizure types. In one, she would become stiff, jerk all over, and mumble with eyes rolled back. In others, she would take a pen and jab herself or complain of intense pain for up to 20 min. Postictally, she would be confused, but amnestic for the seizure. Between seizures, she was often disoriented, confused, and inappropriate, and showed frequent epileptic activities on EEG monitoring in bilateral temporal regions. MRI and CAT scans (Fig. 4) showed a calcified cavernous hemangioma in
Fig. 3. Progressive calcification at two sites in Patient 1. Two focal areas of injury developed in an 8 y/o boy with graft versus host disease became calcified from the center of each lesion over the next few years. These T2-weighted MRI images (top panel) change from bright to dark as the lesions become more calcified. CAT scans shown in the bottom panels before and after disodium etidronate treatment did not change, but clearly show the calcifications as white areas.
these new, late-appearing symptoms were caused and/or exacerbated by the calcifications. One year later, his seizure frequency increased to 4/day and he developed inappropriate behaviors (seen as a peak in seizures and headaches in Fig. 5 months 6 – 9). He was
Fig. 4. Left occipital calcification at the site of a cavernous hemangioma in Patient 2. The MRI shows this as dark, while the unchanged CAT scans on the bottom panels show the calcifications as white.
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J.A. Loeb et al. / Journal of the Neurological Sciences 243 (2006) 77 – 81
the left occipital region. She failed to respond to a number of anti-epileptic medications including carbamazepine, gabapentin, phenytoin, and phenobarbital.
reduction in calcification size was detected for either patient.
5. Discussion 4. Results 5.1. A new disease and its treatment? Baseline seizure and headache frequencies were plotted as days/month with either seizures or headaches for each patient (Fig. 5). Compared to baseline levels, both patients had significant reductions in their symptoms (a = 0.01), including their inappropriate behaviors, after initiation of treatment A, which was disodium etidronate for both patients. These improvements had an initial lag of 2 –3 months, but appeared to be long-lasting even during the subsequent placebo treatment. Most remarkably, Patient 1 had a significant reduction of his headaches from 10.1 days/month at baseline to 4.5 days/month with disodium etidronate. Patient 2 had improved seizure control from 3.6 days/month at baseline to 2.0 days/month with treatment, a 45% reduction. Patient 1 also had a reduction in seizure frequency from 3.2 days/month at baseline to 2.1 days/month, a 34% reduction. Seizures and headaches were concomitant in Patient 1, suggesting a physiological relationship between the seizures and the headaches. As shown in the CAT scans in Figs. 3 and 4, no
Based on these two patients and previously published reports [5,6], we hypothesize that focal calcific deposits within the brain are not benign and lead to neurological dysfunction. Patient 1 developed progressive symptoms of seizures and headaches coincident with progressive calcification of focal cerebral lesions 1– 2 years following an unknown neurological illness. This patient also developed perilesional edema surrounding the larger of the calcified lesions in the setting of frequent partial seizures, suggesting a direct relationship between the calcified lesion and his seizures [7]. We also propose that neurological symptoms associated with brain calcifications can be reduced with the bone drug disodium editronate. Patient 1 had reduced seizure and headache frequencies and Patient 2 had reduced seizures with the bisphosphonate. While these are clearly early findings, disodium etidronate treatment was associated with a seizure reduction that exceeds many add-on anticonvulsant therapies (10 – 29%) [8,9], but does not produce the cognitive side effects seen with most anticonvulsants. Disodium etidronate treatment of a patient with Fahr’s Disease (left panel of Fig. 1), where calcifications are restricted mostly to the basal ganglia, showed a similar, delayed, but lasting improvement in parkinsonian symptoms [6]. Despite the large number of patients that have cerebral calcifications, there is little data from the literature on whether the calcifications themselves are harmful and warrant treatment. To date, the most extensively studied disease that has linked calcification to recurrent seizures is neurocysticercosis [5]. A recent study from India found that while not all patients develop recurrent seizures following initial brain infection, patients that later develop punctuate calcifications are more likely to develop recurrent seizures [4]. Another study using magnetization transfer MRI further refines this by suggesting that calcifications with surrounding gliosis are more likely to become epileptic [10]. On the other hand, a study from Brazil in patients with mesial temporal lobe sclerosis found no significant differences in cognitive performances in those with calcifications from neurocysticercosis and hippocampal sclerosis compared to those with hippocampal sclerosis alone [11]. 5.2. Calcium, neurons, and bisphosphonates
Fig. 5. Double-blind cross-over study with disodium etitronate. The number of days/month with seizures or headaches for Patient 1, and seizures for Patient 2, is shown before and during disodium etidronate (A), and placebo (B) treatments.
Previous studies have implicated calcium channels in the generation of seizure activity; however, calcium channel blockers have not been therapeutically effective in epilepsy
J.A. Loeb et al. / Journal of the Neurological Sciences 243 (2006) 77 – 81
as they have been for headaches [12]. High concentrations of calcium are also known to promote cell death through excitotoxic mechanisms [13]. Here we have postulated and provided some initial testing for the novel use of bisphosphonate drugs for brain calcifications because of their use for disease of bone and ectopic calcifications elsewhere in the body [14]. Disodium etidronate prevents calcium phosphate breakdown, inhibits the precipitation of calcium phosphate, blocks the transformation of amorphous calcium phosphate into hydroxyapatite, and delays aggregation of apatite crystals into larger clusters [14]. In the brain, bisphosphonates can reach brain calcifications through break down of the blood brain barrier [15]. There, the drug may bind calcifications with high affinity, protecting neurons from toxic calcium levels that promote excitability and death. 5.3. The next steps The natural history of brain calcifications are difficult to predict as are the development of related neurological symptoms. Prospective, longitudinal studies that directly relate neurological symptoms to the formation of macroscopic calcifications as well as large-scale clinical trails with bisphosphonates to both prevent and treat cerebral calcifications could be an effective approach to treat patients with brain stones. This may be of particular relevance in the infectious brain diseases such as neurocysticercosis, that commonly develop multiple calcific deposits often associated with life-long seizures.
Acknowledgments We thank Procter and Gamble Pharmaceuticals for providing the disodium etitronate and placebo for this study and for valuable discussions.
81
References [1] Davis RL, Robertson DM. Textbook of neuropathology. 2nd ed. Baltimore’ Williams and Wilkins; 1991 [ed.]. [2] Lowenthal A, Bruyn GW. Striopallidodentate calcification. Handb Clin Neurol 1968;6:712 – 6. [3] Smeyers-Verbeke J, Michotte Y, Pelsmaeckers J, Lowenthal A, Massart DL, Dekegel D, et al. The chemical composition of idiopathic nonarteriosclerotic cerebral calcifications. Neurology 1975; 25(1):48 – 57. [4] Thussu A, Arora A, Prabhakar S, Lal V, Sawhney IM. Acute symptomatic seizures due to single CT lesions: how long to treat with antiepileptic drugs? Neurol India 2002;50(2):141 – 4. [5] Nash TE, Del Brutto OH, Butman JA, Corona T, Delgado-Escueta A, Duron RM, et al. Calcific neurocysticercosis and epileptogenesis. Neurology 2004;62(11):1934 – 8. [6] Loeb JA. Functional improvement in a patient with cerebral calcinosis using a bisphosphonate. Mov Disord 1998;13(2):345 – 9. [7] Nash TE, Patronas NJ. Edema associated with calcified lesions in neurocysticercosis. Neurology 1999;53(4):777 – 81. [8] Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res 2001;47(1 – 2):17 – 25. [9] Deckers CL, Knoester PD, de Haan GJ, Keyser A, Renier WO, Hekster YA. Selection criteria for the clinical use of the newer antiepileptic drugs. CNS Drugs 2003;17(6):405 – 21. [10] Agarwal A, Raghav S, Husain M, Kumar R, Gupta RK. Epilepsy with focal cerebral calcification: role of magnetization transfer MR imaging. Neurol India 2004;52(2):197 – 9. [11] Terra-Bustamante VC, Coimbra ER, Rezek KO, Escorsi-Rosset SR, Guarnieri R, Dalmagro CL, et al. Cognitive performance of patients with mesial temporal lobe epilepsy and incidental calcified neurocysticercosis. J Neurol Neurosurg Psychiatry 2005;76(8):1080 – 3. [12] Chaisewikul R, Baillie N, Marson AG. Calcium antagonists as an addon therapy for drug-resistant epilepsy. Cochrane Database Syst Rev(4):CD002750. [13] Sattler R, Tymianski M. Molecular mechanisms of calcium-dependent excitotoxicity. J Mol Med 2000;78(1):3 – 13. [14] Fleisch H. Bisphosphonates: a new class of drugs in diseases of bone and calcium metabolism. Recent Results Cancer Res 1989;116:1 – 28. [15] Hui C, Lau KK. Intracranial Tc99m MDP uptake in Sturge – Weber syndrome. Australas Radiol 2003;47(1):75 – 7.