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Cor pulmonale in a patient with Brown–Vialetto–Van Laere syndrome: A case report
Journal of the Neurological Sciences 300 (2011) 155–156
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Cor pulmonale in a patient with Brown–Vialetto–Van Laere syndrome: A case report Francisco Pereira da Silva-Júnior a,⁎, Rafael de Deus Moura b, Sérgio Rosemberg b, Paulo Eurípedes Marchiori a, Luiz Henrique Martins Castro a a b
Department of Neurology, Universidade de São Paulo, São Paulo, Brazil Department of Pathology, Universidade de São Paulo, São Paulo, Brazil
a r t i c l e
i n f o
Article history: Received 2 June 2010 Received in revised form 2 October 2010 Accepted 6 October 2010 Available online 5 November 2010 Keywords: Brown–Vialetto–Van Laere Pulmonary heart disease Motor neuron disease
a b s t r a c t Brown–Vialetto–Van Laere syndrome (BVVLS) is a rare neurological disease characterized by sensorineural hearing loss and multiple cranial nerve palsies, usually involving the VIIth and IXth to XIIth cranial nerves. We describe the clinical and pathological features of a 33-year-old woman with BVVLS. The patient developed progressive exertional dyspnea, with clinical and laboratory findings of right-sided heart failure and pulmonary hypertension. She developed status epilepticus in the setting of cardiac deterioration and respiratory infection, and died of cardiogenic and septic shock. Autopsy disclosed bilateral neuronal loss and gliosis in the inferior colliculi, locus coeruleus and facial and vestibular nuclei. Cor pulmonale is a complication of hypoventilation-induced hypoxia and hypercapnia and had not yet been reported in BVVLS. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Brown–Vialetto–Van Laere syndrome (BVVLS), also known as progressive pontobulbar palsy with deafness, is a rare condition characterized by progressive sensorineural hearing loss and multiple cranial nerve palsies, usually involving the VIIth and IXth to XIIth cranial nerves [1]. About sixty cases have been reported since the original description in 1894 [2–4]. Non-neurological features, such as diabetes insipidus, delayed puberty and hypogonadism, have been also been reported in BVVLS [2]. Cardiac complications have not yet been described [2]. We report the clinical and pathological findings of a patient with BVVLS who developed cor pulmonale. 2. Case report A 33-year-old woman presented with progressive bilateral hearing loss in childhood. At the age of 15 years, she complained of dysarthria. About 5 years later, dysphagia and loss of facial expression ensued. She had no history of epilepsy or of a sleep disorder. Her parents were consanguineous and parented 14 children. Two brothers and four sisters also presented hearing loss. Both brothers and one sister died of unknown causes at the ages of 18, 24 and 34. Neurological examination revealed bilateral visual acuity of 20/30, with normal optic discs and eye movements. Bilateral masticatory, facial, pharyngeal and sternocleidomastoid muscle weakness were
⁎ Corresponding author. Rua Dr Melo Alves, 55, Apto 32, Cerqueira César, São Paulo, SP, CEP 01417-010, Brazil. Tel.: +55 11 82025480. E-mail address: [email protected] (F.P. da Silva-Júnior). 0022-510X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.10.010
noted. The tongue was atrophic, with fasciculations. Limb strength, pinprick, temperature and vibration senses, as well as coordination were normal. Deep tendon reflexes were normal in the upper and brisk in the lower extremities, with downgoing plantar reflexes. MiniMental State Examination score was 22/30 (seven years of education). Routine complete blood counts, biochemistry, thyroid function tests, folate and B12 vitamin levels were normal. Audiometry showed a moderate bilateral sensorineural hearing loss. Videolaryngoscopy disclosed bilateral vocal chord paresis. Brain magnetic resonance imaging and cerebrospinal fluid (CSF) analysis were unremarkable. Nerve conduction studies showed mild denervation in the proximal muscle groups of the upper and lower limbs and mild to moderate in the distal muscle groups. There was evidence of mild to moderate denervation in the Vth and XIth cranial nerve motor territory and moderate to severe in the VIIth and XIIth cranial nerve motor territory, bilaterally. Motor nerve conduction velocities and sensory action potentials were normal. A muscle biopsy obtained from the biceps showed fiber-type grouping with type I fiber predominance, consistent with neurogenic changes. Seven months after initial admission, the patient developed progressive exertion dyspnea. Four months later she presented with dyspnea to moderate activity, generalized edema and jugular ingurgitation. Arterial blood gases showed hypoxia and compensated respiratory acidosis (pH 7.36, pO2 42.2, pCO2 65.4, HCO3 36.2, BE 8.1 and SatO2 77%). Chest X-ray and electrocardiogram were suggestive of right cardiac chamber enlargement. An echocardiogram showed moderate right atrial and ventricular enlargement, moderate tricuspid regurgitation and pulmonary arterial hypertension (estimated pulmonary systolic pressure of 52 mm Hg), with normal left ventricular size and function. The patient was admitted to the intensive care unit and clarythromycin and ceftriaxone were empirically initiated for
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F.P. da Silva-Júnior et al. / Journal of the Neurological Sciences 300 (2011) 155–156
presumptive pulmonary infection (purulent sputum, fever and increase of C-reactive protein from 1.06 to 42.6 mg/dL). Episodes of sleep apnea were witnessed. The patient was placed under noninvasive nocturnal ventilatory support with continuous positive airway pressure (CPAP). Her condition deteriorated rapidly and a polysomnographic study could not be performed. She developed status epilepticus, requiring oral intubation and ventilatory support. At this time, laboratory findings showed metabolic alkalosis (pH 7.67, pO2 56.7, pCO2 39.7, HCO3 44.8, BE 22 and SatO2 95.9) and hypophosphataemia (serum phosphate 0.4, normal range 2.5–4.5 mg/dL). EEG disclosed continuous bursts of multifocal sharp waves, at times diffusely distributed, intermixed with brief periods of diffuse background attenuation, indicative of electrographic status epilepticus. Brain computed tomography and a repeat CSF analysis were normal. Seizures were refractory to correction of the underlying metabolic abnormalities and intravenous administration of benzodiazepines (diazepam and midazolam), phenytoin and phenobarbital. Although clinical and electrographic seizure control was later achieved with the initiation of a continuous intravenous thiopental drip, achieving a burst-suppression pattern, the patient did not regain consciousness and eventually died of a mixed (cardiogenic and septic) shock (pneumonia and urinary tract infection). Postmortem examination revealed a brain weight of 1258 g. There was bilateral neuronal loss and gliosis in the inferior colliculi, locus coeruleus and facial and vestibular nuclei. Additional findings were myocardial fibrosis and bilateral bronchopneumonia foci. 3. Discussion The clinical presentation in this patient and prolonged disease course, with early onset sensorineural hearing loss, followed by signs of progressive upper cranial nerve involvement are distinctive of BVVLS [5]. Additional investigations excluded other possible etiologies. The patient's family history strongly suggests an autosomal recessive inherited disease (parental consanguinity and seven out of 14 siblings affected with hearing loss). Recently, a recessive gene mutation (C20orf54) on chromosome 20p13 was associated with this condition [6]. Molecular diagnosis could not be performed in our case. It is intriguing that a locus on 20p13 was identified in a family with autosomal dominant amyotrophic lateral sclerosis (ALS) [7]. Advances in the understanding of BVVLS pathophysiology may help to shed light on the etiology of ALS. The clinical course in BVVLS is variable. Disability may develop rapidly [8] or in a slow progressive fashion [9]. Some patients may remain clinically stable for many years [10]. Spontaneous clinical and electrophysiological improvement has also been reported [11]. Our patient experienced progressive breathing difficulties, with clinical and laboratory findings of right-sided heart failure and pulmonary hypertension. To our knowledge, cor pulmonale has not been described in BVVLS. Despite the short duration of respiratory complaints, myocardial fibrosis was found on autopsy, suggesting a long-term asymptomatic respiratory disorder and cardiac overload. It is well established that hypoxia is the primary cause of pulmonary hypertension in many diseases [12]. Our patient presented
with hypoxia and chronic CO2 retention, probably as a result of hypoventilation in the awake state and sleep apnea. Diaphragmatic weakness leading to hypoventilation is a well known feature of BVVLS, but sleep apnea has only recently been better characterized and is predominantly central in origin [9]. Brainstem respiratory center involvement and, conceivably, respiratory muscle weakness are the likely underlying causes of respiratory failure in our patient. Epilepsy and seizures have been described in two cases of BVVLS [13,14]. Our patient did not have a previous history of epilepsy or seizures, but developed status epilepticus in the setting of a clinical decompensation, suggestive of an acute symptomatic status epilepticus. This has already been described in BVVLS [5]. Seizures and status epilepticus can occur in critically ill patients as a result of primary neurological insult and critical illness [15]. In our case, acute hypoxia and metabolic derangements were the most probable culprits for triggering status epilepticus. We describe the development of a cardiopulmonary complication in a patient with BVVLS: cor pulmonale secondary to hypoventilationinduced chronic hypoxia and hypercapnia. Physicians caring for BVVLS patients should monitor the patient's respiratory function and recognize early signs of respiratory deterioration.
References [1] Sathasivam S, O'Sullivan S, Nicolson A, Tilley PJ, Shaw PJ. Brown–Vialetto–Van Laere syndrome: case report and literature review. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:277–81. [2] Sathasivam S. Brown–Vialetto–Van Laere syndrome. Orphanet J Rare Dis 2008;3:9 Available from: http://www.ojrd.com/content/3/1/9 (acessed on November 15, 2009). [3] Fell D. Anesthesia in Brown–Vialetto–Van Laere syndrome. Paediatr Anaesth 2009;19:1130–8. [4] Dakhil FO, Bensreiti SM, Zew MH. Pontobulbar palsy and sensorineural deafness (Brown–Vialetto-van Laere syndrome): the first case from Libya. Amyotroph Lateral Scler 2010;11:397–8. [5] Alberca R, Montero C, Ibañez A, Segura DI, Miranda-Nieves G. Progressive Bulbar Paralysis associated with neural deafness. Arch Neurol 1980;37:214–6. [6] Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin JP, et al. Brown– Vialetto–van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in C20orf54. Am J Hum Genet 2003;86:485–9. [7] Sapp PC, Hosler BA, McKenna-Yasek D, Chin W, Gann A, Genise H, et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet 2003;73:397–403. [8] Descatha A, Goddet S, Aboab J, Allary J, Gergereau A, Baer M, et al. Cardiac arrest in a patient with Brown–Vialetto–Van Laere syndrome. Amyotroph Lateral Scler 2006;7:187–8. [9] Miao J, Li H, Lin H, Su C, Liu Y, Lei G, et al. Severe sleep-disordered breathing in a patient with Brown–Vialetto–Van Laere syndrome: polysomnographic findings. J Neurol Sci 2007;263:214–7. [10] Prabhu HV, Brown MJ. Brown–Vialetto–Van Laere syndrome: a rare syndrome in otology. J Laryngol Otol 2005;119:470–2. [11] De Grandis D, Passadore P, Chinaglia M, Brazzo F, Ravenni R, Cudia P. Clinical features and neurophysiological follow-up in a case of Brown–Vialetto–Van Laere syndrome. Neuromuscul Disord 2005;15:565–8. [12] Newman JH. Pulmonary hypertension. Am J Respir Crit Care Med 2005;172: 1072–7. [13] Vialetto E. Contributo alla forma ereditaria della paralisi bulbare progressive. Riv Sper Freniat 1936;40:1–24. [14] Van Laere JE. Un nouveau cas de paralysie bulbo-pontine chronique progressive avec surdité. Rev Neurol 1977;133:119–24. [15] Mirski MA, Varelas PN. Seizures and status epilepticus in the critically ill. Crit Care Clin 2008;24:115–47.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Cor pulmonale in a patient with Brown–Vialetto–Van Laere syndrome: A case report Francisco Pereira da Silva-Júnior a,⁎, Rafael de Deus Moura b, Sérgio Rosemberg b, Paulo Eurípedes Marchiori a, Luiz Henrique Martins Castro a a b
Department of Neurology, Universidade de São Paulo, São Paulo, Brazil Department of Pathology, Universidade de São Paulo, São Paulo, Brazil
a r t i c l e
i n f o
Article history: Received 2 June 2010 Received in revised form 2 October 2010 Accepted 6 October 2010 Available online 5 November 2010 Keywords: Brown–Vialetto–Van Laere Pulmonary heart disease Motor neuron disease
a b s t r a c t Brown–Vialetto–Van Laere syndrome (BVVLS) is a rare neurological disease characterized by sensorineural hearing loss and multiple cranial nerve palsies, usually involving the VIIth and IXth to XIIth cranial nerves. We describe the clinical and pathological features of a 33-year-old woman with BVVLS. The patient developed progressive exertional dyspnea, with clinical and laboratory findings of right-sided heart failure and pulmonary hypertension. She developed status epilepticus in the setting of cardiac deterioration and respiratory infection, and died of cardiogenic and septic shock. Autopsy disclosed bilateral neuronal loss and gliosis in the inferior colliculi, locus coeruleus and facial and vestibular nuclei. Cor pulmonale is a complication of hypoventilation-induced hypoxia and hypercapnia and had not yet been reported in BVVLS. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Brown–Vialetto–Van Laere syndrome (BVVLS), also known as progressive pontobulbar palsy with deafness, is a rare condition characterized by progressive sensorineural hearing loss and multiple cranial nerve palsies, usually involving the VIIth and IXth to XIIth cranial nerves [1]. About sixty cases have been reported since the original description in 1894 [2–4]. Non-neurological features, such as diabetes insipidus, delayed puberty and hypogonadism, have been also been reported in BVVLS [2]. Cardiac complications have not yet been described [2]. We report the clinical and pathological findings of a patient with BVVLS who developed cor pulmonale. 2. Case report A 33-year-old woman presented with progressive bilateral hearing loss in childhood. At the age of 15 years, she complained of dysarthria. About 5 years later, dysphagia and loss of facial expression ensued. She had no history of epilepsy or of a sleep disorder. Her parents were consanguineous and parented 14 children. Two brothers and four sisters also presented hearing loss. Both brothers and one sister died of unknown causes at the ages of 18, 24 and 34. Neurological examination revealed bilateral visual acuity of 20/30, with normal optic discs and eye movements. Bilateral masticatory, facial, pharyngeal and sternocleidomastoid muscle weakness were
⁎ Corresponding author. Rua Dr Melo Alves, 55, Apto 32, Cerqueira César, São Paulo, SP, CEP 01417-010, Brazil. Tel.: +55 11 82025480. E-mail address: [email protected] (F.P. da Silva-Júnior). 0022-510X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2010.10.010
noted. The tongue was atrophic, with fasciculations. Limb strength, pinprick, temperature and vibration senses, as well as coordination were normal. Deep tendon reflexes were normal in the upper and brisk in the lower extremities, with downgoing plantar reflexes. MiniMental State Examination score was 22/30 (seven years of education). Routine complete blood counts, biochemistry, thyroid function tests, folate and B12 vitamin levels were normal. Audiometry showed a moderate bilateral sensorineural hearing loss. Videolaryngoscopy disclosed bilateral vocal chord paresis. Brain magnetic resonance imaging and cerebrospinal fluid (CSF) analysis were unremarkable. Nerve conduction studies showed mild denervation in the proximal muscle groups of the upper and lower limbs and mild to moderate in the distal muscle groups. There was evidence of mild to moderate denervation in the Vth and XIth cranial nerve motor territory and moderate to severe in the VIIth and XIIth cranial nerve motor territory, bilaterally. Motor nerve conduction velocities and sensory action potentials were normal. A muscle biopsy obtained from the biceps showed fiber-type grouping with type I fiber predominance, consistent with neurogenic changes. Seven months after initial admission, the patient developed progressive exertion dyspnea. Four months later she presented with dyspnea to moderate activity, generalized edema and jugular ingurgitation. Arterial blood gases showed hypoxia and compensated respiratory acidosis (pH 7.36, pO2 42.2, pCO2 65.4, HCO3 36.2, BE 8.1 and SatO2 77%). Chest X-ray and electrocardiogram were suggestive of right cardiac chamber enlargement. An echocardiogram showed moderate right atrial and ventricular enlargement, moderate tricuspid regurgitation and pulmonary arterial hypertension (estimated pulmonary systolic pressure of 52 mm Hg), with normal left ventricular size and function. The patient was admitted to the intensive care unit and clarythromycin and ceftriaxone were empirically initiated for
156
F.P. da Silva-Júnior et al. / Journal of the Neurological Sciences 300 (2011) 155–156
presumptive pulmonary infection (purulent sputum, fever and increase of C-reactive protein from 1.06 to 42.6 mg/dL). Episodes of sleep apnea were witnessed. The patient was placed under noninvasive nocturnal ventilatory support with continuous positive airway pressure (CPAP). Her condition deteriorated rapidly and a polysomnographic study could not be performed. She developed status epilepticus, requiring oral intubation and ventilatory support. At this time, laboratory findings showed metabolic alkalosis (pH 7.67, pO2 56.7, pCO2 39.7, HCO3 44.8, BE 22 and SatO2 95.9) and hypophosphataemia (serum phosphate 0.4, normal range 2.5–4.5 mg/dL). EEG disclosed continuous bursts of multifocal sharp waves, at times diffusely distributed, intermixed with brief periods of diffuse background attenuation, indicative of electrographic status epilepticus. Brain computed tomography and a repeat CSF analysis were normal. Seizures were refractory to correction of the underlying metabolic abnormalities and intravenous administration of benzodiazepines (diazepam and midazolam), phenytoin and phenobarbital. Although clinical and electrographic seizure control was later achieved with the initiation of a continuous intravenous thiopental drip, achieving a burst-suppression pattern, the patient did not regain consciousness and eventually died of a mixed (cardiogenic and septic) shock (pneumonia and urinary tract infection). Postmortem examination revealed a brain weight of 1258 g. There was bilateral neuronal loss and gliosis in the inferior colliculi, locus coeruleus and facial and vestibular nuclei. Additional findings were myocardial fibrosis and bilateral bronchopneumonia foci. 3. Discussion The clinical presentation in this patient and prolonged disease course, with early onset sensorineural hearing loss, followed by signs of progressive upper cranial nerve involvement are distinctive of BVVLS [5]. Additional investigations excluded other possible etiologies. The patient's family history strongly suggests an autosomal recessive inherited disease (parental consanguinity and seven out of 14 siblings affected with hearing loss). Recently, a recessive gene mutation (C20orf54) on chromosome 20p13 was associated with this condition [6]. Molecular diagnosis could not be performed in our case. It is intriguing that a locus on 20p13 was identified in a family with autosomal dominant amyotrophic lateral sclerosis (ALS) [7]. Advances in the understanding of BVVLS pathophysiology may help to shed light on the etiology of ALS. The clinical course in BVVLS is variable. Disability may develop rapidly [8] or in a slow progressive fashion [9]. Some patients may remain clinically stable for many years [10]. Spontaneous clinical and electrophysiological improvement has also been reported [11]. Our patient experienced progressive breathing difficulties, with clinical and laboratory findings of right-sided heart failure and pulmonary hypertension. To our knowledge, cor pulmonale has not been described in BVVLS. Despite the short duration of respiratory complaints, myocardial fibrosis was found on autopsy, suggesting a long-term asymptomatic respiratory disorder and cardiac overload. It is well established that hypoxia is the primary cause of pulmonary hypertension in many diseases [12]. Our patient presented
with hypoxia and chronic CO2 retention, probably as a result of hypoventilation in the awake state and sleep apnea. Diaphragmatic weakness leading to hypoventilation is a well known feature of BVVLS, but sleep apnea has only recently been better characterized and is predominantly central in origin [9]. Brainstem respiratory center involvement and, conceivably, respiratory muscle weakness are the likely underlying causes of respiratory failure in our patient. Epilepsy and seizures have been described in two cases of BVVLS [13,14]. Our patient did not have a previous history of epilepsy or seizures, but developed status epilepticus in the setting of a clinical decompensation, suggestive of an acute symptomatic status epilepticus. This has already been described in BVVLS [5]. Seizures and status epilepticus can occur in critically ill patients as a result of primary neurological insult and critical illness [15]. In our case, acute hypoxia and metabolic derangements were the most probable culprits for triggering status epilepticus. We describe the development of a cardiopulmonary complication in a patient with BVVLS: cor pulmonale secondary to hypoventilationinduced chronic hypoxia and hypercapnia. Physicians caring for BVVLS patients should monitor the patient's respiratory function and recognize early signs of respiratory deterioration.
References [1] Sathasivam S, O'Sullivan S, Nicolson A, Tilley PJ, Shaw PJ. Brown–Vialetto–Van Laere syndrome: case report and literature review. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:277–81. [2] Sathasivam S. Brown–Vialetto–Van Laere syndrome. Orphanet J Rare Dis 2008;3:9 Available from: http://www.ojrd.com/content/3/1/9 (acessed on November 15, 2009). [3] Fell D. Anesthesia in Brown–Vialetto–Van Laere syndrome. Paediatr Anaesth 2009;19:1130–8. [4] Dakhil FO, Bensreiti SM, Zew MH. Pontobulbar palsy and sensorineural deafness (Brown–Vialetto-van Laere syndrome): the first case from Libya. Amyotroph Lateral Scler 2010;11:397–8. [5] Alberca R, Montero C, Ibañez A, Segura DI, Miranda-Nieves G. Progressive Bulbar Paralysis associated with neural deafness. Arch Neurol 1980;37:214–6. [6] Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin JP, et al. Brown– Vialetto–van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in C20orf54. Am J Hum Genet 2003;86:485–9. [7] Sapp PC, Hosler BA, McKenna-Yasek D, Chin W, Gann A, Genise H, et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet 2003;73:397–403. [8] Descatha A, Goddet S, Aboab J, Allary J, Gergereau A, Baer M, et al. Cardiac arrest in a patient with Brown–Vialetto–Van Laere syndrome. Amyotroph Lateral Scler 2006;7:187–8. [9] Miao J, Li H, Lin H, Su C, Liu Y, Lei G, et al. Severe sleep-disordered breathing in a patient with Brown–Vialetto–Van Laere syndrome: polysomnographic findings. J Neurol Sci 2007;263:214–7. [10] Prabhu HV, Brown MJ. Brown–Vialetto–Van Laere syndrome: a rare syndrome in otology. J Laryngol Otol 2005;119:470–2. [11] De Grandis D, Passadore P, Chinaglia M, Brazzo F, Ravenni R, Cudia P. Clinical features and neurophysiological follow-up in a case of Brown–Vialetto–Van Laere syndrome. Neuromuscul Disord 2005;15:565–8. [12] Newman JH. Pulmonary hypertension. Am J Respir Crit Care Med 2005;172: 1072–7. [13] Vialetto E. Contributo alla forma ereditaria della paralisi bulbare progressive. Riv Sper Freniat 1936;40:1–24. [14] Van Laere JE. Un nouveau cas de paralysie bulbo-pontine chronique progressive avec surdité. Rev Neurol 1977;133:119–24. [15] Mirski MA, Varelas PN. Seizures and status epilepticus in the critically ill. Crit Care Clin 2008;24:115–47.