Parkinsonism and Related Disorders 20 (2014) 651e654
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): Results from a four years follow-up Giovanni Cossu a, *, Giovanni Abbruzzese b, Gildo Matta c, Daniela Murgia a, Maurizio Melis a, Valeria Ricchi a, Renzo Galanello d,1, Susanna Barella d, Raffaella Origa d, Manuela Balocco e, Elisa Pelosin b, Roberta Marchese b, Uberto Ruffinengo f, Gian Luca Forni e a
Neurology Department, “G. Brotzu” General Hospital, Cagliari, Italy Department of Neurosciences, University of Genoa, Italy Radiology Department, “G. Brotzu” General Hospital, Cagliari, Italy d Ospedale Regionale Microcitemia, University of Cagliari, Cagliari, Italy e Centro della Microcitemia e Anemie Congenite-Haematology, Galliera Hospital, Genoa, Italy f Neuroradiology Unit, Galliera Hospital, Genoa, Italy b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 January 2014 Received in revised form 19 February 2014 Accepted 2 March 2014
Objective: To evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA. Methods: 6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15 mg/kg po bid. They were assessed by UPDRS/III and UDRS scales and blinded video rating, performed at baseline and every six months. All patients underwent brain MRI at baseline and during follow up. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence. Results: After 48 months of treatment clinical rating scales and blinded video rating indicated a stabilization in motor symptoms in 5/6 Pts. In the same subjects MRI evaluation showed reduced hypointensity in the globus pallidus (GP); quantitative assessment confirmed a significant increment in the T2* value, and hence reduction of the iron content of the GP. Conclusion: The data from our 4-years follow-up study confirm the safety of DFP as a chelator agent for iron accumulation. The clinical stabilization observed in 5/6 of our patients suggests that DFP may be a reasonable therapeutic option for the treatment of the neurological manifestations linked with iron accumulation and neurodegeneration, especially in adult patients at early stage of the disease. (Clinicaltrials.gov identifier: NTC00907283). Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: PKAN NBIA Iron Deferiprone Magnetic resonance imaging
Deferiprone (DFP) is an oral active bidentate iron chelator effective in the lowering of intracellular iron. Its use is authorized for the treatment of iron overload in patients affected by thalassemia major (not suitable for deferoxamine). Its chemicalephysical characteristics (low molecular weight, favorable octanol/water
* Corresponding author. Neurology Department, AOB “G. Brotzu” General Hospital, P.le Ricchi, 1, 09134 Cagliari, Italy. Tel./fax: þ39 070539639. E-mail addresses: [email protected], [email protected] (G. Cossu). 1 Deceased. http://dx.doi.org/10.1016/j.parkreldis.2014.03.002 1353-8020/Ó 2014 Elsevier Ltd. All rights reserved.
partition coefficient, neutral charge) guarantee good drug permeability through the bloodebrain barrier [1]. NBIA (Neurodegeneration with Brain Iron Accumulation) is a class of neurodegenerative diseases that features a prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic deposition of iron in the basal ganglia [2,3]. PKAN (NBIA subtype 1) is the most common of NBIA with a typical MRI finding (the pallidal “eye-of-the-tiger sign”). While there is currently no cure for PKAN, promising researches offer new perspectives of treatment. The results of our previous one-yeartreatment study [4,5] suggested that DFP might be effective in
652
G. Cossu et al. / Parkinsonism and Related Disorders 20 (2014) 651e654
Table 1 Clinical and genetical data of the patients. Patient
Sex
Age (years)
Disease Duration (years)
1
M
52
7
2 3
F M
29 34
6 14
4
F
32
16
5
F
22
11
6
F
40
27
Clinical features
Diagnosis
MRI
Follow-up (months)
Cranial dystonia parkinsonism Multifocal dystonia Multifocal dystonia parkinsonism Multifocal dystonia parkinsonism Multifocal dystonia parkinsonism Multifocal dystonia parkinsonism retinitis pigmentosa
NBIA
T2* hypointensities in GP (bilateral)
48
PKAN (Pank2 þ) PKAN (Pank2 þ)
T2* hypointensities in GP (bilateral) “tiger eye” T2* hypointensities in GP (bilateral) “tiger eye”
48 48
PKAN (Pank2 þ)
T2* hypointensities in GP (bilateral) “tiger eye”
48
PKAN (Pank2 þ)
T2* hypointensities in GP (bilateral) “tiger eye”
48
PKAN (Pank2 þ)
T2* hypointensities in GP (bilateral) “tiger eye”
36
reverse iron deposition and improve neurological manifestations in patients with NBIA. Due to these encouraging results we extended the treatment period. Here we report the clinical and neuroradiological findings of 6 patients (5 with genetically confirmed PKAN). Five completed 4 years of treatment, one received DFP for three years. 1. Patients and methods After the conclusion of the first one-year pilot study [5] the participants were invited to join an extension study (2009e2012) for an additional three-year followup treatment. 5 out of 6 patients accepted and have been currently in treatment since 2008. One additional patient (Pt. 6) was enrolled later (2009) in the present study and recently completed 36 months of treatment. The extension trial was approved by the E.O. Ospedali Galliera Ethics Committee and the local Ethics Committee at the Cagliari center. All participants gave written informed consent. All 6 patients included in this report (5 with genetically confirmed PKAN, 1 with idiopathic NBIA; Table 1) received DFP solution (Apopharm, Toronto, ON, Canada) at 15 mg/kg po bid. For inclusion criteria, procedures and safety monitoring see Ref. [4]. Follow-up visits were performed every six months. All patients were videotaped and assessed by neurologists expert in movement disorders from the Department of Neurosciences (University of Genoa) and from the Department of Neurology (Brotzu Hospital of Cagliari). The Unified Parkinson’s Disease Rating Scale (UPDRS/III e Motor Section) and the Unified Dystonia Rating Scale (UDRS) were administered at baseline and during follow up. An independent neurologist made a blinded evaluation of the videotapes.
2. Magnetic resonance imaging All patients underwent brain MRI at baseline and every 12 months during follow up. MRI examinations were carried out on a 1.5 T Sigma unit (GE Medical Systems, Milwaukee, WI) using a phased array head coil. The protocol included sequences for morphologic and quantitative assessment. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence (field of view 24 cm, 255 224 matrix, slice thickness 5 mm, gap 3 mm, TR: 400 ms, 10 echoes at TE from 3.5 ms to 54 ms, flip angle 50 , acquisition time 4 min) to acquire each axial brain slice at ten echo time. Quantitative T2* maps were calculated off-line using a custom
made reconstruction algorithm (FuncTool v. 5.2.09, GE Medical Systems). Two oval ROI (10 mm2) were manually drawn by a single neuroradiologist within the boundaries of the right and left globus pallidus at different levels, on consecutive sections. The signal intensity was measured at each echo time. The final T2* value was the mean of the results determined for each level. As internal control, several (2 or more, depending on the size of the region) circular ROIs of 24 mm2 were drawn in the white matter of cerebral and cerebellar hemispheres, where iron concentration is assumed to be low, and in thalamic nuclei. In order to determine the reproducibility of the quantitative measurement in the two centers, a study of a phantom containing samples of known different concentrations of iron was performed in Cagliari and Genoa. 3. Results 3.1. Clinical changes Clinical rating scales demonstrated an improvement or a stabilization of symptoms (according to both clinical scores and blinded video rating) in 3 patients (Pts. 1,4,6). Two patients (Pts. 2,3) were judged as mild worsened by the blinded video raters but the clinical scores were unchanged or mild improved. Only one patient (Pt. 5) was assessed as definitively worsened by both clinical scores and blinded video evaluation (Table 2). For 2 patients (Pts. 3,4) we have additional information as their video and clinical data are available from 2004 (time of diagnosis), that is 4 years before the treatment onset. Clinical scales (Fig. 1) clearly show a difference in the rate of symptoms progression before and after 2008 (time of treatment onset). About the MRI results (Table 2), a long term reduction (Pts. 2,3,4,6) or stabilization (Pt. 1) of pallidal iron overload was observed in the large majority of the patients. Multiparametric T2* brain MRI images of Pt. 2. (Fig. 2), only given as an example, shows the
Table 2 Clinical (rating scales and video rating) and radiological findings (MRI) of the patients at baseline and during the follow-up (24 and 48 months). Patient
1 2 3 4 5 6
UPDRS motor score
UDRS global score
Blinded video rating
MRI T2*weighted GE values in GPi (ms)
Basal
24
48
Basal
24
48
24
48
Basal (ReL)
24 (ReL)
48 (ReL)
13 13 29 47 31 25
6 9 21 43 34 21
13 9 23 47 39 20 (36 mo)
5 5 13 21 16 30
4 6 13 21 24 28
4 6 13 22 54 27 (36 mo)
Improved moderately Mild worsening Mild worsening Unchanged Worsened Unchanged
Improved moderately Unchanged Mild worsening Unchanged Worsened Unchanged (36 mo)
e 23e25 19e21 20e20 e 21e18
54e42 30e30 22e20 23e25 22e26 37e42
50e49 30e35 23e25 24e25 14e13 42e44 (36 mo)
G. Cossu et al. / Parkinsonism and Related Disorders 20 (2014) 651e654
Fig. 1. Clinical scales of Pts. 3 and 4. (A: Unified Dystonia Rating Scale B: motor UPDRS) at baseline (2004), treatment onset (2008) and at the end of study (2012).
significant reduction of bilateral pallidal iron overload after 4 years treatment. Only in a single case (Pt. 5), the one who also demonstrated a clinical deterioration, the pallidal iron increased. 4. Conclusion Despite major advances in our understanding of the neurodegenerative process in NBIA spectrum of illnesses, to date non-novel disease-modifying therapies have been shown to provide significant benefits for patients who suffer from these severe disorders. Even though iron overload does not probably represent the initiating factor triggering neurodegeneration, it still remains one of the main steps of the pathological cascade and, hitherto, the more effectively targetable factor for therapeutical purposes since the introduction of DFP, able to specifically reduce the brain iron excess.
653
In NBIA and particularly in PKAN patients, DFP proved to be safe, well tolerated and effective in lowering CNS iron (as measured by MRI), but its ability to determine a clear clinical benefit is still debated [5e9]. The main causes of this uncertainty consist of the infrequency of NBIA (which does not allow to design large placebo-controlled studies) and the brief period of treatment so far considered. Zorzi et al. [6] used DFP (25 mg/kg/day) in 9 patients (all with early-onset typical PKAN and considerable clinical impairment). They observed that the drug was able to significantly reduce brain iron accumulation without concomitant clinical improvement over a six-month study period. It can be considered that longer observation time is needed to detect the treatment effectiveness in reverse or halting symptoms, also taking into account the variability of the natural history of the NBIA spectrum of illnesses. With this goal in mind, we monitored for a long time the effect of DFP in a fairly homogeneous group of patients (5 out of 6 have a genetically confirmed PKAN, all of them with slowprogressive adult onset dystonia-parkinsonism as the main clinical feature). After 4 years of treatment (only in one case the time of observation was 36 months), the drug proved to be well tolerated and safe, without any serious hematologic or neurologic adverse event. But the main finding of our work is the enduring improvement or stabilization of symptoms with a significant clinicaleradiological correlation. In our patients MRI demonstrated a persistent mitigation of the pallidal iron accumulation in 5 out of 6 cases which correlated with a persistent improvement or stabilization of motor symptoms (in 1 case) or a clinical stabilization (in 4 cases). In two of these patients we have clinical data available since 4 years before the treatment onset: in both of them we were able to detect a clear different progression of symptoms before and after DFP, which could provide a further suggestion of the drug effectiveness in slowing the disease progression. Only in a single patient a worsening of both MRI and clinical findings was observed. She presented the youngest age at symptoms onset (11 ys.) and was one of the most disabled at the treatment beginning. In PKAN, as well as in others forms of NBIA, iron accumulation is strongly related with age [10]. Therefore it is not surprising that patients with the “adult-onset” subtype benefit more from iron chelation treatment than the “childhoodonset” form. Moreover, our findings suggest that the treatment efficacy enhances when it is started right after diagnosis, when symptoms are less severe and neurodegeneration probably less advanced.
Fig. 2. A,B: Multiparametric color T2* brain MRI images of Pt. 2. Two oval ROI define the right and left globus pallidus, at treatment onset (A) and after 4 years (B). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
654
G. Cossu et al. / Parkinsonism and Related Disorders 20 (2014) 651e654
In conclusion, the data from our study underline the long-term safety and tolerability of DFP as a chelator agent for intra and extraneuronal iron accumulation. The enduring stabilization of symptoms observed in the large majority of our patients over a prolonged observation period, together with the MRI data, suggest that treatment with DFP may be effective in the management of neurological manifestations linked with iron accumulation. However, these results need to be confirmed in a larger randomized study with a longer observation time. References [1] Fredenburg AM, Sethi RK, Allen DD, Yokel RA. The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2 dimethyl-, 1,2 diethyl-, and 1-[ethan-1’ol]-2-methyl-3-hydroxypyridin-4-one in the rat. Toxicology 1996;108(3):191e9. [2] Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46(2):73e80. [3] Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP. Genetics and pathophysiology of neurodegeneration with brain iron accumulation (NBIA). Curr Neuropharmacol 2013 Jan;11(1):59e79.
[4] Ferrochelating treatment in patients affected by neurodegeneration with brain iron accumulation (NBIA). http://ClinicalTrials.gov/show/NCT00907283. [5] Abbruzzese G, Cossu G, Balocco M, Marchese R, Murgia D, Melis M, et al. A pilot trial of deferiprone for neurodegeneration with brain iron accumulation. Haematologica 2011 Nov;96(11):1708e11. [6] Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, et al. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord 2011 Aug 1;26(9):1756e9. [7] Forni GL, Balocco M, Cremonesi L, Abbruzzese G, Parodi RC, Marchese R. Regression of symptoms after selective iron chelation therapy in a case of neurodegeneration with brain iron accumulation. Mov Disord 2008 Apr 30;23(6):904e7. [8] Kwiatkowski A, Ryckewaert G, Jissendi Tchofo P, Moreau C, Villaume I, Chinnery PF, et al. Long-term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation. Parkinsonism Relat Disord 2012 Jan;18(1):110e2. [9] Pratini NR, Sweeters N, Vichinsky E, Neufeld JA. Treatment of classic pantothenate kinase-associated neurodegeneration with deferiprone and intrathecal baclofen. Am J Phys Med Rehabil 2013 Aug;92(8):728e33. [10] Vilchez-Abreu C, Roa-Sanchez P, Fermin-Delgado R, Speckter H, Perez-Then E, Oviedo J, et al. “The “eye-of-the-tiger” sign in magnetic resonance: age-related changes. An Radiol México 2013;12(3):189e96.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): Results from a four years follow-up Giovanni Cossu a, *, Giovanni Abbruzzese b, Gildo Matta c, Daniela Murgia a, Maurizio Melis a, Valeria Ricchi a, Renzo Galanello d,1, Susanna Barella d, Raffaella Origa d, Manuela Balocco e, Elisa Pelosin b, Roberta Marchese b, Uberto Ruffinengo f, Gian Luca Forni e a
Neurology Department, “G. Brotzu” General Hospital, Cagliari, Italy Department of Neurosciences, University of Genoa, Italy Radiology Department, “G. Brotzu” General Hospital, Cagliari, Italy d Ospedale Regionale Microcitemia, University of Cagliari, Cagliari, Italy e Centro della Microcitemia e Anemie Congenite-Haematology, Galliera Hospital, Genoa, Italy f Neuroradiology Unit, Galliera Hospital, Genoa, Italy b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 January 2014 Received in revised form 19 February 2014 Accepted 2 March 2014
Objective: To evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA. Methods: 6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15 mg/kg po bid. They were assessed by UPDRS/III and UDRS scales and blinded video rating, performed at baseline and every six months. All patients underwent brain MRI at baseline and during follow up. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence. Results: After 48 months of treatment clinical rating scales and blinded video rating indicated a stabilization in motor symptoms in 5/6 Pts. In the same subjects MRI evaluation showed reduced hypointensity in the globus pallidus (GP); quantitative assessment confirmed a significant increment in the T2* value, and hence reduction of the iron content of the GP. Conclusion: The data from our 4-years follow-up study confirm the safety of DFP as a chelator agent for iron accumulation. The clinical stabilization observed in 5/6 of our patients suggests that DFP may be a reasonable therapeutic option for the treatment of the neurological manifestations linked with iron accumulation and neurodegeneration, especially in adult patients at early stage of the disease. (Clinicaltrials.gov identifier: NTC00907283). Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: PKAN NBIA Iron Deferiprone Magnetic resonance imaging
Deferiprone (DFP) is an oral active bidentate iron chelator effective in the lowering of intracellular iron. Its use is authorized for the treatment of iron overload in patients affected by thalassemia major (not suitable for deferoxamine). Its chemicalephysical characteristics (low molecular weight, favorable octanol/water
* Corresponding author. Neurology Department, AOB “G. Brotzu” General Hospital, P.le Ricchi, 1, 09134 Cagliari, Italy. Tel./fax: þ39 070539639. E-mail addresses: [email protected], [email protected] (G. Cossu). 1 Deceased. http://dx.doi.org/10.1016/j.parkreldis.2014.03.002 1353-8020/Ó 2014 Elsevier Ltd. All rights reserved.
partition coefficient, neutral charge) guarantee good drug permeability through the bloodebrain barrier [1]. NBIA (Neurodegeneration with Brain Iron Accumulation) is a class of neurodegenerative diseases that features a prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic deposition of iron in the basal ganglia [2,3]. PKAN (NBIA subtype 1) is the most common of NBIA with a typical MRI finding (the pallidal “eye-of-the-tiger sign”). While there is currently no cure for PKAN, promising researches offer new perspectives of treatment. The results of our previous one-yeartreatment study [4,5] suggested that DFP might be effective in
652
G. Cossu et al. / Parkinsonism and Related Disorders 20 (2014) 651e654
Table 1 Clinical and genetical data of the patients. Patient
Sex
Age (years)
Disease Duration (years)
1
M
52
7
2 3
F M
29 34
6 14
4
F
32
16
5
F
22
11
6
F
40
27
Clinical features
Diagnosis
MRI
Follow-up (months)
Cranial dystonia parkinsonism Multifocal dystonia Multifocal dystonia parkinsonism Multifocal dystonia parkinsonism Multifocal dystonia parkinsonism Multifocal dystonia parkinsonism retinitis pigmentosa
NBIA
T2* hypointensities in GP (bilateral)
48
PKAN (Pank2 þ) PKAN (Pank2 þ)
T2* hypointensities in GP (bilateral) “tiger eye” T2* hypointensities in GP (bilateral) “tiger eye”
48 48
PKAN (Pank2 þ)
T2* hypointensities in GP (bilateral) “tiger eye”
48
PKAN (Pank2 þ)
T2* hypointensities in GP (bilateral) “tiger eye”
48
PKAN (Pank2 þ)
T2* hypointensities in GP (bilateral) “tiger eye”
36
reverse iron deposition and improve neurological manifestations in patients with NBIA. Due to these encouraging results we extended the treatment period. Here we report the clinical and neuroradiological findings of 6 patients (5 with genetically confirmed PKAN). Five completed 4 years of treatment, one received DFP for three years. 1. Patients and methods After the conclusion of the first one-year pilot study [5] the participants were invited to join an extension study (2009e2012) for an additional three-year followup treatment. 5 out of 6 patients accepted and have been currently in treatment since 2008. One additional patient (Pt. 6) was enrolled later (2009) in the present study and recently completed 36 months of treatment. The extension trial was approved by the E.O. Ospedali Galliera Ethics Committee and the local Ethics Committee at the Cagliari center. All participants gave written informed consent. All 6 patients included in this report (5 with genetically confirmed PKAN, 1 with idiopathic NBIA; Table 1) received DFP solution (Apopharm, Toronto, ON, Canada) at 15 mg/kg po bid. For inclusion criteria, procedures and safety monitoring see Ref. [4]. Follow-up visits were performed every six months. All patients were videotaped and assessed by neurologists expert in movement disorders from the Department of Neurosciences (University of Genoa) and from the Department of Neurology (Brotzu Hospital of Cagliari). The Unified Parkinson’s Disease Rating Scale (UPDRS/III e Motor Section) and the Unified Dystonia Rating Scale (UDRS) were administered at baseline and during follow up. An independent neurologist made a blinded evaluation of the videotapes.
2. Magnetic resonance imaging All patients underwent brain MRI at baseline and every 12 months during follow up. MRI examinations were carried out on a 1.5 T Sigma unit (GE Medical Systems, Milwaukee, WI) using a phased array head coil. The protocol included sequences for morphologic and quantitative assessment. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence (field of view 24 cm, 255 224 matrix, slice thickness 5 mm, gap 3 mm, TR: 400 ms, 10 echoes at TE from 3.5 ms to 54 ms, flip angle 50 , acquisition time 4 min) to acquire each axial brain slice at ten echo time. Quantitative T2* maps were calculated off-line using a custom
made reconstruction algorithm (FuncTool v. 5.2.09, GE Medical Systems). Two oval ROI (10 mm2) were manually drawn by a single neuroradiologist within the boundaries of the right and left globus pallidus at different levels, on consecutive sections. The signal intensity was measured at each echo time. The final T2* value was the mean of the results determined for each level. As internal control, several (2 or more, depending on the size of the region) circular ROIs of 24 mm2 were drawn in the white matter of cerebral and cerebellar hemispheres, where iron concentration is assumed to be low, and in thalamic nuclei. In order to determine the reproducibility of the quantitative measurement in the two centers, a study of a phantom containing samples of known different concentrations of iron was performed in Cagliari and Genoa. 3. Results 3.1. Clinical changes Clinical rating scales demonstrated an improvement or a stabilization of symptoms (according to both clinical scores and blinded video rating) in 3 patients (Pts. 1,4,6). Two patients (Pts. 2,3) were judged as mild worsened by the blinded video raters but the clinical scores were unchanged or mild improved. Only one patient (Pt. 5) was assessed as definitively worsened by both clinical scores and blinded video evaluation (Table 2). For 2 patients (Pts. 3,4) we have additional information as their video and clinical data are available from 2004 (time of diagnosis), that is 4 years before the treatment onset. Clinical scales (Fig. 1) clearly show a difference in the rate of symptoms progression before and after 2008 (time of treatment onset). About the MRI results (Table 2), a long term reduction (Pts. 2,3,4,6) or stabilization (Pt. 1) of pallidal iron overload was observed in the large majority of the patients. Multiparametric T2* brain MRI images of Pt. 2. (Fig. 2), only given as an example, shows the
Table 2 Clinical (rating scales and video rating) and radiological findings (MRI) of the patients at baseline and during the follow-up (24 and 48 months). Patient
1 2 3 4 5 6
UPDRS motor score
UDRS global score
Blinded video rating
MRI T2*weighted GE values in GPi (ms)
Basal
24
48
Basal
24
48
24
48
Basal (ReL)
24 (ReL)
48 (ReL)
13 13 29 47 31 25
6 9 21 43 34 21
13 9 23 47 39 20 (36 mo)
5 5 13 21 16 30
4 6 13 21 24 28
4 6 13 22 54 27 (36 mo)
Improved moderately Mild worsening Mild worsening Unchanged Worsened Unchanged
Improved moderately Unchanged Mild worsening Unchanged Worsened Unchanged (36 mo)
e 23e25 19e21 20e20 e 21e18
54e42 30e30 22e20 23e25 22e26 37e42
50e49 30e35 23e25 24e25 14e13 42e44 (36 mo)
G. Cossu et al. / Parkinsonism and Related Disorders 20 (2014) 651e654
Fig. 1. Clinical scales of Pts. 3 and 4. (A: Unified Dystonia Rating Scale B: motor UPDRS) at baseline (2004), treatment onset (2008) and at the end of study (2012).
significant reduction of bilateral pallidal iron overload after 4 years treatment. Only in a single case (Pt. 5), the one who also demonstrated a clinical deterioration, the pallidal iron increased. 4. Conclusion Despite major advances in our understanding of the neurodegenerative process in NBIA spectrum of illnesses, to date non-novel disease-modifying therapies have been shown to provide significant benefits for patients who suffer from these severe disorders. Even though iron overload does not probably represent the initiating factor triggering neurodegeneration, it still remains one of the main steps of the pathological cascade and, hitherto, the more effectively targetable factor for therapeutical purposes since the introduction of DFP, able to specifically reduce the brain iron excess.
653
In NBIA and particularly in PKAN patients, DFP proved to be safe, well tolerated and effective in lowering CNS iron (as measured by MRI), but its ability to determine a clear clinical benefit is still debated [5e9]. The main causes of this uncertainty consist of the infrequency of NBIA (which does not allow to design large placebo-controlled studies) and the brief period of treatment so far considered. Zorzi et al. [6] used DFP (25 mg/kg/day) in 9 patients (all with early-onset typical PKAN and considerable clinical impairment). They observed that the drug was able to significantly reduce brain iron accumulation without concomitant clinical improvement over a six-month study period. It can be considered that longer observation time is needed to detect the treatment effectiveness in reverse or halting symptoms, also taking into account the variability of the natural history of the NBIA spectrum of illnesses. With this goal in mind, we monitored for a long time the effect of DFP in a fairly homogeneous group of patients (5 out of 6 have a genetically confirmed PKAN, all of them with slowprogressive adult onset dystonia-parkinsonism as the main clinical feature). After 4 years of treatment (only in one case the time of observation was 36 months), the drug proved to be well tolerated and safe, without any serious hematologic or neurologic adverse event. But the main finding of our work is the enduring improvement or stabilization of symptoms with a significant clinicaleradiological correlation. In our patients MRI demonstrated a persistent mitigation of the pallidal iron accumulation in 5 out of 6 cases which correlated with a persistent improvement or stabilization of motor symptoms (in 1 case) or a clinical stabilization (in 4 cases). In two of these patients we have clinical data available since 4 years before the treatment onset: in both of them we were able to detect a clear different progression of symptoms before and after DFP, which could provide a further suggestion of the drug effectiveness in slowing the disease progression. Only in a single patient a worsening of both MRI and clinical findings was observed. She presented the youngest age at symptoms onset (11 ys.) and was one of the most disabled at the treatment beginning. In PKAN, as well as in others forms of NBIA, iron accumulation is strongly related with age [10]. Therefore it is not surprising that patients with the “adult-onset” subtype benefit more from iron chelation treatment than the “childhoodonset” form. Moreover, our findings suggest that the treatment efficacy enhances when it is started right after diagnosis, when symptoms are less severe and neurodegeneration probably less advanced.
Fig. 2. A,B: Multiparametric color T2* brain MRI images of Pt. 2. Two oval ROI define the right and left globus pallidus, at treatment onset (A) and after 4 years (B). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
654
G. Cossu et al. / Parkinsonism and Related Disorders 20 (2014) 651e654
In conclusion, the data from our study underline the long-term safety and tolerability of DFP as a chelator agent for intra and extraneuronal iron accumulation. The enduring stabilization of symptoms observed in the large majority of our patients over a prolonged observation period, together with the MRI data, suggest that treatment with DFP may be effective in the management of neurological manifestations linked with iron accumulation. However, these results need to be confirmed in a larger randomized study with a longer observation time. References [1] Fredenburg AM, Sethi RK, Allen DD, Yokel RA. The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2 dimethyl-, 1,2 diethyl-, and 1-[ethan-1’ol]-2-methyl-3-hydroxypyridin-4-one in the rat. Toxicology 1996;108(3):191e9. [2] Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46(2):73e80. [3] Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP. Genetics and pathophysiology of neurodegeneration with brain iron accumulation (NBIA). Curr Neuropharmacol 2013 Jan;11(1):59e79.
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