revue neurologique 171 (2015) 674–684
of artery dissection. Cardiovascular toxicity of anti-VEGF therapies is now acknowledged and anti-VEGF drugs were previously reported in aortic dissection but such complication remains rare and the risk could be enhanced by additional factors. The association of arterial dissection and anti-VEGF drugs can thus appear fortuitous, although a link between both cannot be excluded. Herein, the patient had a moderate hyperhomocysteinemia and chronic inflammation, which are both recognized as minor risk factor for spontaneous CAD. We hypothesized that these factors could have been responsible of a tear of the vascular wall and anti-VEGF drugs could have impaired the mechanisms of repair, favouring carotid artery dissection. To conclude, while we cannot rule out a fortuitous association, this case report emphasize the potential role of VEGF in the pathophysiology of CAD through an impairment of vascular wall properties.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
references
[1] Ropert S, Vignaux O, Mir O, Goldwasser F. VEGF pathway inhibition by anticancer agent sunitinib and susceptibility to atherosclerosis plaque disruption. Invest New Drugs 2011;29(6):1497–9. [2] Kloss M, Grond-Ginsbach C, Pezzini A, Metso TM, Metso AJ, Debette S, et al. Stroke in first-degree relatives of patients with cervical artery dissection. Eur J Neurol 2014;21(8):1102–7. [3] Matsuno H, Takei M, Hayashi H, Nakajima K, Ishisaki A, Kozawa O. Simvastatin enhances the regeneration of endothelial cells via VEGF secretion in injured arteries. J Cardiovasc Pharmacol 2004;43(3):333–40.
C. Bonnet CHU de Bordeaux, Unite´ neurovasculaire, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France I. Sibon* CHU de Bordeaux, Unite´ neurovasculaire, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France Universite´ Bordeaux 2, 146, rue Le´o-Saignat, 33000 Bordeaux, France UMR CNRS 5231, 146, rue Le´o-Saignat, 33000 Bordeaux, France *Corresponding author at: CHU de Bordeaux, Unite´ neurovasculaire, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France. E-mail address: [email protected] (I. Sibon) Received 1st November Received in revised form 13 February Accepted 16 March Available online 23 April
2014 2015 2015 2015
http://dx.doi.org/10.1016/j.neurol.2015.03.010 0035-3787/# 2015 Elsevier Masson SAS. All rights reserved.
679
Parkinsonism in a patient with Leber hereditary optic neuropathy (LHON) Syndrome parkinsonien et neuropathie optique he´re´ditaire de Leber (LHON) A 32-year-old Caucasian started his illness when his vision deteriorated in a few weeks, and he remained almost totally blind. Leber hereditary optic neuropathy (LHON) had already been diagnosed in his mother and a first cousin from his maternal side. At 69, he developed parkinsonism and was treated with classic levodopa replacement without any improvement. When investigated 1 year later, he presented with akinesia and rigidity, slightly predominating on the right side but no tremor. He also had axial dystonia with camptocormia. Cerebral MRI showed features of leukoencephalopathy, predominating in the occipital areas. A subclinical neuropathy of axonal type was diagnosed at electrophysiological study, and a neuromuscular biopsy was performed. Paraffin embedded fragments from the peroneous brevis muscle showed no modifications, and there were no ragged red fibers (RRF) on frozen specimens. The superficial peroneal nerve presented a marked loss of myelinated nerve fibers (4.569/mm2), as well as several clusters of regenerating nerve fibers and numerous damaged unmyelinated fibers. None abnormal mitochondria (mt) was noticed at ultrastructural examination of muscle and nerve. Four years later, LHON was definitely diagnosed by identifying a homoplasmic 11778 G!A mutation in the mtDNA by PCR-RFLP and sequencing performed on total DNA from peripheral blood. A few cases of parkinsonism have been reported in patients with mitochondriopathy, either primary with a mutation in the mtDNA or secondary to mutation in nuclear DNA. A 34-year-old man, alcoholic and heavy smoker, presented a bilateral subacute optic neuropathy and parkinsonism. He also had a supranuclear ophthalmoplegia, and MRI disclosed increased intensity of signals in the dorsal parts of both striatum. A 3460 mtDNA mutation was evidenced on blood samples, and this case was reported as Leber’s ‘‘plus’’ disease [1]. Another patient, with A8344G mutation in tRNALys characteristic of MERRF, presented parkinsonism with ataxia and RRF on frozen muscle specimens [2]. In a family with multisystem degeneration, four maternally inherited patients presented a prominent levodopa responsive parkinsonism, associated with progressive external ophthalmoplegia in one of them. Two other parkinsonian patients had also dystonia and dementia. One patient died at 59 years and post-mortem brain examination evidenced marked loss of pigmented neurons in the substantia nigra without any Lewy bodies. A missense mutation was present at position 11778 of the mtDNA [3]. On the other hand, a few cases of parkinsonism with ophthalmoplegia have been observed in cases of mutations in nuclear DNA, mainly in POLG1 gene. Most of them were familial with chronic external ophthalmoplegia, dysarthria, and sensory peripheral neuropathy. Frozen muscle specimens stained for cytochrome c oxydase (COX) and succinate deshydrogenase (SDH) showed several fibers with marked RRF and absence of COX activity. In a typical case,
680
revue neurologique 171 (2015) 674–684
multiple mtDNA microdeletions were present at PCR-RFLP studies [4]. In such a setting, rare cases are concerned with a mutation in the TWINKLE gene [5]. Parkinsonism and dystonia observed in our patient were probably related to the subjacent mitochondrial cytopathy as was exemplified in some other cases [1–3], and discussed at length recently [6].
Ence´phalite herpe´tique en postpartum complique´e d’un he´matome ce´re´bral Postpartum herpetic encephalitis complicated by cerebral hematoma
Disclosure of interest 1. The authors declare that they have no conflicts of interest concerning this article.
references
[1] Thobois S, Vighetto A, Grochowicki M, Godinot C, Broussolle E, Aimard G. Maladie de Leber « Plus » : neuropathie optique, syndrome parkinsonien et ophtalmople´gie supranucle´aire. Rev Neurol 1997;153(10):595–8. [2] Horvath R, Kley RA, Lochmuller H, Vorgerd M. Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys. Neurology 2007;68:56–8. [3] Simon DK, Pulst SM, Sutton JP, Browne SE, Beal MF, Johns DR. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology 1999;53:1787–93. [4] Bandettini di Poggio M, Nesti C, Bruno C, Meschini MC, Schenone A, Santorelli FM. Dopamine-agonist responsive parkinsonism in a patient with the SANDO syndrome caused by POLG mutation. BMC Med Genet 2013;14:105. [5] Baloh RH, Salavaggione E, Milbrandt J, Pestronk A. Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase Twinkle. Arch Neurol 2007;64(7):998–1000. [6] Vital A, Lepreux S, Vital C. Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum. J Peripher Nerv Syst 2014;19(4):333–42.
C. Vitala,b J. Juliena M.-L. Martin-Negriera,b A. Laguenya X. Ferrera A. Vitala,b,* a Universite´ Bordeaux, Hoˆpital Pellegrin, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France b Universite´ Bordeaux, Institut des Maladies Neurode´ge´ne´ratives, UMR 5293, 146, rue Le´o-Saignat, 33076 Bordeaux, France *Corresponding author at: Service de Pathologie, Hoˆpital Pellegrin, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France. E-mail address: [email protected] (J. Julien) Received 20 January Received in revised form 9 March Accepted 16 March Available online 24 April
2015 2015 2015 2015
http://dx.doi.org/10.1016/j.neurol.2015.03.011 0035-3787/# 2015 Elsevier Masson SAS. All rights reserved.
Introduction
L’ence´phalite herpe´tique est le chef de file des ence´phalites virales de l’adulte immunocompe´tent, ses manifestations cliniques sont variables : fie`vre, convulsion, troubles de conscience ou de comportement et meˆme psychiatriques. L’he´matome ce´re´bral est une complication extreˆmement rare dont on rapporte un cas.
2.
Observation
Il s’agit d’une femme de 28 ans, multipare, au 4e mois du postpartum qui avait dans ses ante´ce´dents une psychose puerpe´rale et un pe`re suivi pour une psychose chronique. Elle avait pre´sente´ au 3e mois du post-partum des troubles de comportement a` type de ne´gligence vestimentaire, une insomnie, un de´lire de perse´cution, des troubles de me´moire ante´rograde et des ce´phale´es. L’examen a` son admission avait trouve´ une patiente agite´e, de´soriente´e dans le temps et l’espace, apyre´tique a` 37 8C et une tension arte´rielle normale. Il y avait aussi une raideur de la nuque et une hypertonie musculaire ge´ne´ralise´e sans de´ficit. La TDM ce´re´brale avait montre´ la pre´sence d’une discre`te hypodensite´ temporale droite sans prise de contraste (Fig. 1A). La ponction lombaire avait retire´ un LCR d’aspect clair avec les caracte´ristiques suivantes : 2 leucocytes/mm3, 980 he´maties/mm3, albuminorrachie : 0,23 g/L, glucorrachie : 0,58 g/L (rapport glucorrachie/glyce´mie supe´rieur a` 0,5), examen direct ne´gatif, culture ste´rile, la PCR de l’ADN de l’HSV dans le LCR e´tait ` la NFS il y avait une ane´mie positive pour l’HSV1. A hypochrome microcytaire mais pas d’hyperleucocytose, le taux de CRP e´tait normal. La se´rologie syphilitique et le bilan de tuberculose e´taient ne´gatifs. Le bilan he´patique et hydroe´lectrolytique e´taient normaux. L’acyclovir a` 10 mg/kg/8 h avait e´te´ administre´ en intraveineux pendant 15 jours. Les troubles de comportement avaient re´gresse´, mais devant la persistance des ce´phale´es on avait re´alise´ une 2e TDM ce´re´brale qui avait montre´ la pre´sence d’une le´sion soustentorielle droite spontane´ment hyperdense en rapport avec un he´matome (Fig. 1B). L’angioIRM n’avait pas objective´ d’anomalie vasculaire.
3.
Discussion
L’incidence de l’ence´phalite herpe´tique, due dans 90 % des cas a` l’HSV1, est de 1 a` 3 cas/1 million d’habitants par an [1]. Ses principaux symptoˆmes sont : fie`vre 92 %, troubles de la personnalite´ 85 %, troubles du langage 76 %, dysautonomie
of artery dissection. Cardiovascular toxicity of anti-VEGF therapies is now acknowledged and anti-VEGF drugs were previously reported in aortic dissection but such complication remains rare and the risk could be enhanced by additional factors. The association of arterial dissection and anti-VEGF drugs can thus appear fortuitous, although a link between both cannot be excluded. Herein, the patient had a moderate hyperhomocysteinemia and chronic inflammation, which are both recognized as minor risk factor for spontaneous CAD. We hypothesized that these factors could have been responsible of a tear of the vascular wall and anti-VEGF drugs could have impaired the mechanisms of repair, favouring carotid artery dissection. To conclude, while we cannot rule out a fortuitous association, this case report emphasize the potential role of VEGF in the pathophysiology of CAD through an impairment of vascular wall properties.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
references
[1] Ropert S, Vignaux O, Mir O, Goldwasser F. VEGF pathway inhibition by anticancer agent sunitinib and susceptibility to atherosclerosis plaque disruption. Invest New Drugs 2011;29(6):1497–9. [2] Kloss M, Grond-Ginsbach C, Pezzini A, Metso TM, Metso AJ, Debette S, et al. Stroke in first-degree relatives of patients with cervical artery dissection. Eur J Neurol 2014;21(8):1102–7. [3] Matsuno H, Takei M, Hayashi H, Nakajima K, Ishisaki A, Kozawa O. Simvastatin enhances the regeneration of endothelial cells via VEGF secretion in injured arteries. J Cardiovasc Pharmacol 2004;43(3):333–40.
C. Bonnet CHU de Bordeaux, Unite´ neurovasculaire, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France I. Sibon* CHU de Bordeaux, Unite´ neurovasculaire, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France Universite´ Bordeaux 2, 146, rue Le´o-Saignat, 33000 Bordeaux, France UMR CNRS 5231, 146, rue Le´o-Saignat, 33000 Bordeaux, France *Corresponding author at: CHU de Bordeaux, Unite´ neurovasculaire, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France. E-mail address: [email protected] (I. Sibon) Received 1st November Received in revised form 13 February Accepted 16 March Available online 23 April
2014 2015 2015 2015
http://dx.doi.org/10.1016/j.neurol.2015.03.010 0035-3787/# 2015 Elsevier Masson SAS. All rights reserved.
679
Parkinsonism in a patient with Leber hereditary optic neuropathy (LHON) Syndrome parkinsonien et neuropathie optique he´re´ditaire de Leber (LHON) A 32-year-old Caucasian started his illness when his vision deteriorated in a few weeks, and he remained almost totally blind. Leber hereditary optic neuropathy (LHON) had already been diagnosed in his mother and a first cousin from his maternal side. At 69, he developed parkinsonism and was treated with classic levodopa replacement without any improvement. When investigated 1 year later, he presented with akinesia and rigidity, slightly predominating on the right side but no tremor. He also had axial dystonia with camptocormia. Cerebral MRI showed features of leukoencephalopathy, predominating in the occipital areas. A subclinical neuropathy of axonal type was diagnosed at electrophysiological study, and a neuromuscular biopsy was performed. Paraffin embedded fragments from the peroneous brevis muscle showed no modifications, and there were no ragged red fibers (RRF) on frozen specimens. The superficial peroneal nerve presented a marked loss of myelinated nerve fibers (4.569/mm2), as well as several clusters of regenerating nerve fibers and numerous damaged unmyelinated fibers. None abnormal mitochondria (mt) was noticed at ultrastructural examination of muscle and nerve. Four years later, LHON was definitely diagnosed by identifying a homoplasmic 11778 G!A mutation in the mtDNA by PCR-RFLP and sequencing performed on total DNA from peripheral blood. A few cases of parkinsonism have been reported in patients with mitochondriopathy, either primary with a mutation in the mtDNA or secondary to mutation in nuclear DNA. A 34-year-old man, alcoholic and heavy smoker, presented a bilateral subacute optic neuropathy and parkinsonism. He also had a supranuclear ophthalmoplegia, and MRI disclosed increased intensity of signals in the dorsal parts of both striatum. A 3460 mtDNA mutation was evidenced on blood samples, and this case was reported as Leber’s ‘‘plus’’ disease [1]. Another patient, with A8344G mutation in tRNALys characteristic of MERRF, presented parkinsonism with ataxia and RRF on frozen muscle specimens [2]. In a family with multisystem degeneration, four maternally inherited patients presented a prominent levodopa responsive parkinsonism, associated with progressive external ophthalmoplegia in one of them. Two other parkinsonian patients had also dystonia and dementia. One patient died at 59 years and post-mortem brain examination evidenced marked loss of pigmented neurons in the substantia nigra without any Lewy bodies. A missense mutation was present at position 11778 of the mtDNA [3]. On the other hand, a few cases of parkinsonism with ophthalmoplegia have been observed in cases of mutations in nuclear DNA, mainly in POLG1 gene. Most of them were familial with chronic external ophthalmoplegia, dysarthria, and sensory peripheral neuropathy. Frozen muscle specimens stained for cytochrome c oxydase (COX) and succinate deshydrogenase (SDH) showed several fibers with marked RRF and absence of COX activity. In a typical case,
680
revue neurologique 171 (2015) 674–684
multiple mtDNA microdeletions were present at PCR-RFLP studies [4]. In such a setting, rare cases are concerned with a mutation in the TWINKLE gene [5]. Parkinsonism and dystonia observed in our patient were probably related to the subjacent mitochondrial cytopathy as was exemplified in some other cases [1–3], and discussed at length recently [6].
Ence´phalite herpe´tique en postpartum complique´e d’un he´matome ce´re´bral Postpartum herpetic encephalitis complicated by cerebral hematoma
Disclosure of interest 1. The authors declare that they have no conflicts of interest concerning this article.
references
[1] Thobois S, Vighetto A, Grochowicki M, Godinot C, Broussolle E, Aimard G. Maladie de Leber « Plus » : neuropathie optique, syndrome parkinsonien et ophtalmople´gie supranucle´aire. Rev Neurol 1997;153(10):595–8. [2] Horvath R, Kley RA, Lochmuller H, Vorgerd M. Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys. Neurology 2007;68:56–8. [3] Simon DK, Pulst SM, Sutton JP, Browne SE, Beal MF, Johns DR. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology 1999;53:1787–93. [4] Bandettini di Poggio M, Nesti C, Bruno C, Meschini MC, Schenone A, Santorelli FM. Dopamine-agonist responsive parkinsonism in a patient with the SANDO syndrome caused by POLG mutation. BMC Med Genet 2013;14:105. [5] Baloh RH, Salavaggione E, Milbrandt J, Pestronk A. Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase Twinkle. Arch Neurol 2007;64(7):998–1000. [6] Vital A, Lepreux S, Vital C. Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum. J Peripher Nerv Syst 2014;19(4):333–42.
C. Vitala,b J. Juliena M.-L. Martin-Negriera,b A. Laguenya X. Ferrera A. Vitala,b,* a Universite´ Bordeaux, Hoˆpital Pellegrin, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France b Universite´ Bordeaux, Institut des Maladies Neurode´ge´ne´ratives, UMR 5293, 146, rue Le´o-Saignat, 33076 Bordeaux, France *Corresponding author at: Service de Pathologie, Hoˆpital Pellegrin, place Ame´lie-Raba-Le´on, 33076 Bordeaux cedex, France. E-mail address: [email protected] (J. Julien) Received 20 January Received in revised form 9 March Accepted 16 March Available online 24 April
2015 2015 2015 2015
http://dx.doi.org/10.1016/j.neurol.2015.03.011 0035-3787/# 2015 Elsevier Masson SAS. All rights reserved.
Introduction
L’ence´phalite herpe´tique est le chef de file des ence´phalites virales de l’adulte immunocompe´tent, ses manifestations cliniques sont variables : fie`vre, convulsion, troubles de conscience ou de comportement et meˆme psychiatriques. L’he´matome ce´re´bral est une complication extreˆmement rare dont on rapporte un cas.
2.
Observation
Il s’agit d’une femme de 28 ans, multipare, au 4e mois du postpartum qui avait dans ses ante´ce´dents une psychose puerpe´rale et un pe`re suivi pour une psychose chronique. Elle avait pre´sente´ au 3e mois du post-partum des troubles de comportement a` type de ne´gligence vestimentaire, une insomnie, un de´lire de perse´cution, des troubles de me´moire ante´rograde et des ce´phale´es. L’examen a` son admission avait trouve´ une patiente agite´e, de´soriente´e dans le temps et l’espace, apyre´tique a` 37 8C et une tension arte´rielle normale. Il y avait aussi une raideur de la nuque et une hypertonie musculaire ge´ne´ralise´e sans de´ficit. La TDM ce´re´brale avait montre´ la pre´sence d’une discre`te hypodensite´ temporale droite sans prise de contraste (Fig. 1A). La ponction lombaire avait retire´ un LCR d’aspect clair avec les caracte´ristiques suivantes : 2 leucocytes/mm3, 980 he´maties/mm3, albuminorrachie : 0,23 g/L, glucorrachie : 0,58 g/L (rapport glucorrachie/glyce´mie supe´rieur a` 0,5), examen direct ne´gatif, culture ste´rile, la PCR de l’ADN de l’HSV dans le LCR e´tait ` la NFS il y avait une ane´mie positive pour l’HSV1. A hypochrome microcytaire mais pas d’hyperleucocytose, le taux de CRP e´tait normal. La se´rologie syphilitique et le bilan de tuberculose e´taient ne´gatifs. Le bilan he´patique et hydroe´lectrolytique e´taient normaux. L’acyclovir a` 10 mg/kg/8 h avait e´te´ administre´ en intraveineux pendant 15 jours. Les troubles de comportement avaient re´gresse´, mais devant la persistance des ce´phale´es on avait re´alise´ une 2e TDM ce´re´brale qui avait montre´ la pre´sence d’une le´sion soustentorielle droite spontane´ment hyperdense en rapport avec un he´matome (Fig. 1B). L’angioIRM n’avait pas objective´ d’anomalie vasculaire.
3.
Discussion
L’incidence de l’ence´phalite herpe´tique, due dans 90 % des cas a` l’HSV1, est de 1 a` 3 cas/1 million d’habitants par an [1]. Ses principaux symptoˆmes sont : fie`vre 92 %, troubles de la personnalite´ 85 %, troubles du langage 76 %, dysautonomie
