- Email: [email protected]
Treatment of central pontine myelinolysis with thyrotropin-releasing hormone
Presse Med. 2006; 35: 618-20 © 2006, Masson Paris
en ligne sur/ on line on
Clinical case
www.masson.fr/revues/pm
Treatment of central pontine myelinolysis with thyrotropin-releasing hormone Émile F. Zein1, Souheil E. Karaa2, Florence Rollot3, Philippe Blanche3, Raymond E. Chemaly4 1. Internal medicine department, Saint-Joseph Hospital and Medical Center, Saint-Joseph University, Beirut, Lebanon 2. Internal medicine and Intensive care department, Saint-Joseph Hospital, Dora ; Saint-Joseph University, Beirut, Lebanon. 3. Internal medicine department, Cochin University Hospital, Paris (75) 4. Neurology departments, Hotel-Dieu de France, University Hospital, and SaintJoseph Hospital, Dora ; Saint-Joseph University, Beirut, Lebanon.
Correspondence :
Received December 1, 2004 Accepted September 28, 2005
Philippe Blanche, Service de médecine interne, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14. Tél. : 01 58 41 21 23 Fax : 01 58 41 21 00/21 01 [email protected]
■ Summary
■ Résumé
Introduction > Central pontine myelinolysis (CPM), demyelination of the brain stem, is a brain injury apparently due to osmotic forces. There is no consensus for its treatment. Case > We describe here a case of CPM that occurred in a young patient after correction of hyponatremia, its treatment by intravenous thyrotropin-releasing hormone, and its outcome. Discussion > Although very few instances of thyrotropin-releasing hormone treatment for CPM have been described, it appears to be effective and well tolerated. Studies are needed to assess its real efficacy.
Traitement de la myélinolyse centro-pontine par thyrotropin-releasing-hormone Introduction > La myélinolyse centro-pontine (MCP) est souvent due à une lésion cérébrale d’origine osmotique. Il n’existe pas de consensus thérapeutique. Observation > Nous décrivons un cas de MCP au décours de la correction d’une hyponatrémie et qui a été traité par la TRH (ThyrotropinReleasing-Hormone). Discussion > Il n’y a que très peu de cas de MCP traités par TRH, cependant cetraitement semble efficace et bien toléré. Des études sont nécessaires pour évaluer l’efficacité réelle de ce traitement.
618
Zein ÉF, Karaa SE, Rollot F, Blanche P, Chemaly RE. Treatment of central pontine myelinolysis with thyrotropin-releasing hormone. Presse Med. 2006; 35: 618-20 © 2006, Masson, Paris
tome 35 > n° 4 > avril 2006 > cahier 1
A
27-year-old man was admitted to a psychiatric hospital for severe behavior disorders. His medical history included surgery for chronic sinusitis and schizophrenia (onset seven years earlier). Three months before that admission, he presented hallucinations, aggressivity and insomnia. In the four weeks preceding admission, vomiting, sweating, dysuria, reduced eating, and polydipsia were frequent, and in the two weeks before hospitalization, he had many unexplained falls. On admission (16 August, 2002), risperidone, zuclopenthixol, and benzhexol treatment began. The following day, he refused to eat and fell down while walking. Two days later, a perfusion was started, with 1 liter dextrose (2.5%)-saline (0.45%) and 1 liter dextrose-in-water (5%) daily. On the third day, his serum sodium level was 125 mmol/L, potassium 3 mmol/L, and creatinine 203 μmol/L. Fever (38° C) and hypertension (160/100 mm Hg) developed on day 6. He was completely akinetic, with eyes open, but did not react to verbal or painful stimuli. Brainstem reflexes and fundi were normal, and muscle tone was slightly decreased, tending to maintain the passive limb position. He retained urine. Tendon and plantar flexor reflexes were normal. The following day, he was transferred to the intensive care unit in our hospital, where he was slightly more reactive. Routine blood tests were normal, except for elevated serum creatinine (243 μmol/L); serum sodium was 136 mmol/L; his erythrocyte sedimentation rate was 20 mm (first hour); thyroid hormones were normal; vitamin B12 was 128 pg/mL (normal: 180-800). Computed tomography and magnetic resonance imaging of the brain were both normal. Abdominal ultrasound
revealed bilateral hydronephrosis. Cerebrospinal fluid was tested and normal on days 2 and 9 in our hospital. On day 4, he developed respiratory arrest with severe bradycardia. He was immediately intubated and mechanically ventilated. Intravenous acyclovir (10 mg/kg three times daily) was given for 15 days, with parenteral vitamins B1, B6 and B12, unsuccessfully. On day 9, the patient was weaned from the ventilator and extubated. His eyes opened to painful stimuli, he had a blink reflex and normal brainstem and plantar flexor reflexes; tears appeared in his eyes when his mother was present. On day 15, we considered a diagnosis of vasculitis and administered methylprednisolone (500 mg/day intravenously) for three days, but there was no change. Although no infection could be identified, antibiotics were administered for the intermittent fever and were not successful. On day 20, he opened his eyes spontaneously, but there was no plantar flexor reflex response. He was otherwise stable. A new brain MRI revealed central pontine myelinolysis (figure 1). He underwent tracheostomy on day 24 because of persistent secretions and ineffective cough. Because this severe condition failed to improve over a six-week period, we decided on an unusual treatment with thyrotropin-releasing hormone (TRH, UCB Pharma), which began on day 38 (when the drug became available). He received TRH 2 mg daily, in 500 ml of 20% dextrose, in a 2-hour intravenous perfusion, for 5 days. The treatment was well tolerated. On day 46 (1 October), a slight, but definite improvement in his neurological condition was observed: the patient was more alert, turned his head when addressed, and obeyed the request to move his hands. The patient was subsequently transferred to another hospital closer to his home. One month later, the tracheostomy was closed, as he was breathing and swallowing normally, and the fever was gone. He began to move his limbs and to speak well and was oriented in time and space, but still had recurrent vomiting episodes. He was re-admitted to our hospital internal medicine ward on 10 January 2003 and had another 5-day course of TRH 2 mg daily. He was alert, with normal cognitive functions and cranial nerves. His muscle strength was 4/5, except for knee flexion and foot mobility (0/5). Sensitivity and tendon reflexes were normal, without response to plantar stimulation. Painful joints and calcifications severely reduced his mobility, especially because of inadequate physiotherapy. Upper endoscopy revealed esophagitis, hiatus hernia, polyps, and a deep duodenal ulcer (which histologic analysis showed to be benign). Gastrointestinal symptoms improved after treatment for the ulcer and clozapine.
Clinical case
Treatment of central pontine myelinolysis with thyrotropin-releasing hormone
Figure 1 T2-weighted cerebral MRI. Transversal section
tome 35 > n° 4 > avril 2006 > cahier 1
This patient, who was taking antipsychotic drugs, vomiting, sweating, eating little, and polydipsic, was at risk for hyponatremia. The clinical picture at admission was dramatic. The nor-
619
© DR
Discussion
Zein ÉF, Karaa SE, Rollot F, Blanche P, Chemaly RE
mal appearance of the first brain CT scan and MRI, led us to consider catatonia, encephalitis, vasculitis, and metabolic disturbances as possible diagnoses, but 20 days later, the lesions typical of central pontine myelinolysis (CPM) were seen on the repeated MRI. This delayed appearance of CPM on brains scans has been reported elsewhere [1]. Because “osmotic stress” appears to be the precipitant of brain injury in CPM [2], the term “osmotic demyelinization syndrome” is sometimes used to describe pontine myelinolysis [3]. It has been suggested that some individuals may be predisposed to CPM, having inadequate energy provision as well as other factors that result in a proapoptotic drive that renders them susceptible to brain injury from diverse causes [2]. The underlying condition most frequently associated with CPM is chronic alcoholism, but hyponatremia and especially its correction are also common (reported incidence of 21.5%) [3]. Hypokalemia, hypophosphoremia, hypermagnesemia, seizure-induced hypoxemia, and malnutrition with vitamin B deficiency are additional risk factors for brain demyelinization [4,5]. No specific treatment has been proven effective in CPM. TRH was proposed by two Japanese teams, each reporting a good outcome in a patient with CPM secondary to hyponatremia: pro-
gressive recovery began within a few days of TRH (2 mg/day, intravenous) treatment and was complete after two months [6, 7]. We had similar good results in the case of a thirteen-yearold girl with extrapontine myelinolysis of the brain secondary to hyponatremia to whom we administered TRH (0.6 mg/day, intravenous) for 45 days. Improvement began on day 4 and was complete after two months [8]. In those three patients and in the case we report here, neurological condition was very poor and did not change for several weeks before therapy started. Improvement began within a few days of treatment and continued for two months until recovery. It is probable that our patient’s incomplete recovery was due to the long delay before and the briefness of the TRH treatment. TRH’s mechanism of action in brain myelinolysis remains unknown. It may increase cerebral blood flow, especially in the brainstem, and potentiate L-Dopa [7, 8]. Tolerance to TRH is good; side effects are rare and minor (even at higher doses), as seen in the amyotrophic lateral sclerosis trials [9]. In conclusion, TRH is well tolerated and seems to merit trial in central and extrapontine myelinolysis that does not improve with symptomatic treatment. A multicenter study is needed for further assessment of this therapy for this rare disease.
References 1
2
3
620
4
Karp BI, Laureno R. Pontine and extrapontine myelinolysis. A neurologic disorder following rapid correction of hyponatremia. Medicine. 1993; 72 : 359-73. Ashrafian H, Davey P. A review of the causes of central pontine myelinolysis: yet another apoptotic illness? Eur J Neurol. 2001; 8: 103-9. Lampl C, Yazdi K. Central Pontine myelinolysis. Eur Neurol. 2002; 47: 3-10. Leens C, Mukendi R, Foret F, Hacourt A, Devuyst O, Colin IM. Central and extrapontine myelinolysis in a patient in spite of a careful cor-
5
6
7
rection of hyponatremia. Clin Nephrol. 2001; 55: 248-53. Riggs JE, Hogg JP. Central pontine myelinolysis : association with parenteral magnesium administration. Mil Med. 2000; 165: 494-5. Konno S, Nakagawa T, Yoshida T, Hayashibe Y, Maemura T, Goto K et al. A case report of central pontine myelinolysis associated with serum hyperosmolality after open heart surgery. Kyobu Geka. 1993; 46: 150-4. Wakui H,Nishimura S,Watahiki Y, Endo Y, Nakamoto Y, Miura AB. Dramatic recovery from
8
9
neurological deficits in a patient with central pontine myelinolysis following severe hyponatremia. Jpn J Med. 1991; 30: 281-4. Chemaly R, Halaby G, Mohasseb G, Medlej R, Tamraz J, El-Koussa S. Extrapontine myelinolysis: treatment with TRH. Rev Neurol. 1998; 154: 163-5. Brooks BR, Sufit RL, Montgomery GK, Beaulieu DA, Erickson LM. Intravenous thyrotropin-releasing hormone in patients with amyotrophic lateral sclerosis. Neurologic Clinics. 1987; 5: 143-58.
tome 35 > n° 4 > avril 2006 > cahier 1
en ligne sur/ on line on
Clinical case
www.masson.fr/revues/pm
Treatment of central pontine myelinolysis with thyrotropin-releasing hormone Émile F. Zein1, Souheil E. Karaa2, Florence Rollot3, Philippe Blanche3, Raymond E. Chemaly4 1. Internal medicine department, Saint-Joseph Hospital and Medical Center, Saint-Joseph University, Beirut, Lebanon 2. Internal medicine and Intensive care department, Saint-Joseph Hospital, Dora ; Saint-Joseph University, Beirut, Lebanon. 3. Internal medicine department, Cochin University Hospital, Paris (75) 4. Neurology departments, Hotel-Dieu de France, University Hospital, and SaintJoseph Hospital, Dora ; Saint-Joseph University, Beirut, Lebanon.
Correspondence :
Received December 1, 2004 Accepted September 28, 2005
Philippe Blanche, Service de médecine interne, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14. Tél. : 01 58 41 21 23 Fax : 01 58 41 21 00/21 01 [email protected]
■ Summary
■ Résumé
Introduction > Central pontine myelinolysis (CPM), demyelination of the brain stem, is a brain injury apparently due to osmotic forces. There is no consensus for its treatment. Case > We describe here a case of CPM that occurred in a young patient after correction of hyponatremia, its treatment by intravenous thyrotropin-releasing hormone, and its outcome. Discussion > Although very few instances of thyrotropin-releasing hormone treatment for CPM have been described, it appears to be effective and well tolerated. Studies are needed to assess its real efficacy.
Traitement de la myélinolyse centro-pontine par thyrotropin-releasing-hormone Introduction > La myélinolyse centro-pontine (MCP) est souvent due à une lésion cérébrale d’origine osmotique. Il n’existe pas de consensus thérapeutique. Observation > Nous décrivons un cas de MCP au décours de la correction d’une hyponatrémie et qui a été traité par la TRH (ThyrotropinReleasing-Hormone). Discussion > Il n’y a que très peu de cas de MCP traités par TRH, cependant cetraitement semble efficace et bien toléré. Des études sont nécessaires pour évaluer l’efficacité réelle de ce traitement.
618
Zein ÉF, Karaa SE, Rollot F, Blanche P, Chemaly RE. Treatment of central pontine myelinolysis with thyrotropin-releasing hormone. Presse Med. 2006; 35: 618-20 © 2006, Masson, Paris
tome 35 > n° 4 > avril 2006 > cahier 1
A
27-year-old man was admitted to a psychiatric hospital for severe behavior disorders. His medical history included surgery for chronic sinusitis and schizophrenia (onset seven years earlier). Three months before that admission, he presented hallucinations, aggressivity and insomnia. In the four weeks preceding admission, vomiting, sweating, dysuria, reduced eating, and polydipsia were frequent, and in the two weeks before hospitalization, he had many unexplained falls. On admission (16 August, 2002), risperidone, zuclopenthixol, and benzhexol treatment began. The following day, he refused to eat and fell down while walking. Two days later, a perfusion was started, with 1 liter dextrose (2.5%)-saline (0.45%) and 1 liter dextrose-in-water (5%) daily. On the third day, his serum sodium level was 125 mmol/L, potassium 3 mmol/L, and creatinine 203 μmol/L. Fever (38° C) and hypertension (160/100 mm Hg) developed on day 6. He was completely akinetic, with eyes open, but did not react to verbal or painful stimuli. Brainstem reflexes and fundi were normal, and muscle tone was slightly decreased, tending to maintain the passive limb position. He retained urine. Tendon and plantar flexor reflexes were normal. The following day, he was transferred to the intensive care unit in our hospital, where he was slightly more reactive. Routine blood tests were normal, except for elevated serum creatinine (243 μmol/L); serum sodium was 136 mmol/L; his erythrocyte sedimentation rate was 20 mm (first hour); thyroid hormones were normal; vitamin B12 was 128 pg/mL (normal: 180-800). Computed tomography and magnetic resonance imaging of the brain were both normal. Abdominal ultrasound
revealed bilateral hydronephrosis. Cerebrospinal fluid was tested and normal on days 2 and 9 in our hospital. On day 4, he developed respiratory arrest with severe bradycardia. He was immediately intubated and mechanically ventilated. Intravenous acyclovir (10 mg/kg three times daily) was given for 15 days, with parenteral vitamins B1, B6 and B12, unsuccessfully. On day 9, the patient was weaned from the ventilator and extubated. His eyes opened to painful stimuli, he had a blink reflex and normal brainstem and plantar flexor reflexes; tears appeared in his eyes when his mother was present. On day 15, we considered a diagnosis of vasculitis and administered methylprednisolone (500 mg/day intravenously) for three days, but there was no change. Although no infection could be identified, antibiotics were administered for the intermittent fever and were not successful. On day 20, he opened his eyes spontaneously, but there was no plantar flexor reflex response. He was otherwise stable. A new brain MRI revealed central pontine myelinolysis (figure 1). He underwent tracheostomy on day 24 because of persistent secretions and ineffective cough. Because this severe condition failed to improve over a six-week period, we decided on an unusual treatment with thyrotropin-releasing hormone (TRH, UCB Pharma), which began on day 38 (when the drug became available). He received TRH 2 mg daily, in 500 ml of 20% dextrose, in a 2-hour intravenous perfusion, for 5 days. The treatment was well tolerated. On day 46 (1 October), a slight, but definite improvement in his neurological condition was observed: the patient was more alert, turned his head when addressed, and obeyed the request to move his hands. The patient was subsequently transferred to another hospital closer to his home. One month later, the tracheostomy was closed, as he was breathing and swallowing normally, and the fever was gone. He began to move his limbs and to speak well and was oriented in time and space, but still had recurrent vomiting episodes. He was re-admitted to our hospital internal medicine ward on 10 January 2003 and had another 5-day course of TRH 2 mg daily. He was alert, with normal cognitive functions and cranial nerves. His muscle strength was 4/5, except for knee flexion and foot mobility (0/5). Sensitivity and tendon reflexes were normal, without response to plantar stimulation. Painful joints and calcifications severely reduced his mobility, especially because of inadequate physiotherapy. Upper endoscopy revealed esophagitis, hiatus hernia, polyps, and a deep duodenal ulcer (which histologic analysis showed to be benign). Gastrointestinal symptoms improved after treatment for the ulcer and clozapine.
Clinical case
Treatment of central pontine myelinolysis with thyrotropin-releasing hormone
Figure 1 T2-weighted cerebral MRI. Transversal section
tome 35 > n° 4 > avril 2006 > cahier 1
This patient, who was taking antipsychotic drugs, vomiting, sweating, eating little, and polydipsic, was at risk for hyponatremia. The clinical picture at admission was dramatic. The nor-
619
© DR
Discussion
Zein ÉF, Karaa SE, Rollot F, Blanche P, Chemaly RE
mal appearance of the first brain CT scan and MRI, led us to consider catatonia, encephalitis, vasculitis, and metabolic disturbances as possible diagnoses, but 20 days later, the lesions typical of central pontine myelinolysis (CPM) were seen on the repeated MRI. This delayed appearance of CPM on brains scans has been reported elsewhere [1]. Because “osmotic stress” appears to be the precipitant of brain injury in CPM [2], the term “osmotic demyelinization syndrome” is sometimes used to describe pontine myelinolysis [3]. It has been suggested that some individuals may be predisposed to CPM, having inadequate energy provision as well as other factors that result in a proapoptotic drive that renders them susceptible to brain injury from diverse causes [2]. The underlying condition most frequently associated with CPM is chronic alcoholism, but hyponatremia and especially its correction are also common (reported incidence of 21.5%) [3]. Hypokalemia, hypophosphoremia, hypermagnesemia, seizure-induced hypoxemia, and malnutrition with vitamin B deficiency are additional risk factors for brain demyelinization [4,5]. No specific treatment has been proven effective in CPM. TRH was proposed by two Japanese teams, each reporting a good outcome in a patient with CPM secondary to hyponatremia: pro-
gressive recovery began within a few days of TRH (2 mg/day, intravenous) treatment and was complete after two months [6, 7]. We had similar good results in the case of a thirteen-yearold girl with extrapontine myelinolysis of the brain secondary to hyponatremia to whom we administered TRH (0.6 mg/day, intravenous) for 45 days. Improvement began on day 4 and was complete after two months [8]. In those three patients and in the case we report here, neurological condition was very poor and did not change for several weeks before therapy started. Improvement began within a few days of treatment and continued for two months until recovery. It is probable that our patient’s incomplete recovery was due to the long delay before and the briefness of the TRH treatment. TRH’s mechanism of action in brain myelinolysis remains unknown. It may increase cerebral blood flow, especially in the brainstem, and potentiate L-Dopa [7, 8]. Tolerance to TRH is good; side effects are rare and minor (even at higher doses), as seen in the amyotrophic lateral sclerosis trials [9]. In conclusion, TRH is well tolerated and seems to merit trial in central and extrapontine myelinolysis that does not improve with symptomatic treatment. A multicenter study is needed for further assessment of this therapy for this rare disease.
References 1
2
3
620
4
Karp BI, Laureno R. Pontine and extrapontine myelinolysis. A neurologic disorder following rapid correction of hyponatremia. Medicine. 1993; 72 : 359-73. Ashrafian H, Davey P. A review of the causes of central pontine myelinolysis: yet another apoptotic illness? Eur J Neurol. 2001; 8: 103-9. Lampl C, Yazdi K. Central Pontine myelinolysis. Eur Neurol. 2002; 47: 3-10. Leens C, Mukendi R, Foret F, Hacourt A, Devuyst O, Colin IM. Central and extrapontine myelinolysis in a patient in spite of a careful cor-
5
6
7
rection of hyponatremia. Clin Nephrol. 2001; 55: 248-53. Riggs JE, Hogg JP. Central pontine myelinolysis : association with parenteral magnesium administration. Mil Med. 2000; 165: 494-5. Konno S, Nakagawa T, Yoshida T, Hayashibe Y, Maemura T, Goto K et al. A case report of central pontine myelinolysis associated with serum hyperosmolality after open heart surgery. Kyobu Geka. 1993; 46: 150-4. Wakui H,Nishimura S,Watahiki Y, Endo Y, Nakamoto Y, Miura AB. Dramatic recovery from
8
9
neurological deficits in a patient with central pontine myelinolysis following severe hyponatremia. Jpn J Med. 1991; 30: 281-4. Chemaly R, Halaby G, Mohasseb G, Medlej R, Tamraz J, El-Koussa S. Extrapontine myelinolysis: treatment with TRH. Rev Neurol. 1998; 154: 163-5. Brooks BR, Sufit RL, Montgomery GK, Beaulieu DA, Erickson LM. Intravenous thyrotropin-releasing hormone in patients with amyotrophic lateral sclerosis. Neurologic Clinics. 1987; 5: 143-58.
tome 35 > n° 4 > avril 2006 > cahier 1