- Email: [email protected]
Mycophenolate mofetil – as an adjunctive immunosuppressive therapy in refractory myasthenia gravis: The Singapore experience
278
Case reports / Journal of Clinical Neuroscience 14 (2007) 278–281
References 1. Yokota T, Hayashi M, Hirashima F, Mitani M, Tanabe H, Tsukagoshi H. Dysautonomia with acute sensory motor neuropathy. Arch Neurol 1994;51:1022–31. 2. Adachi H, Mukai E, Okuda S, Kawada T. A severe case of acute autonomic and sensory neuropathy. Rinshou Shinkeigaku 1998;38:663–8 [in Japanese with English abstract]. 3. Okada F. Psychiatric aspects of acute pandysautonomia. Eur Arch Psychiatry Clin Neurosci 1990;240:134–5. 4. Nakagawa T, Kumamoto T, Watanabe S, Uchino M, Araki S. A case of acute autonomic, sensory and motor neuropathy. Rinshou Shinkeigaku 1988;28:260–7 [in Japanese with English abstract]. 5. Fujii N, Tabira T, Shibasaki H, Kuroiwa Y, Ohnishi A, Nagaki J. Acute autonomic and sensory neuropathy associated with elevated Epstein-Barr virus antibody titer. J Neurol Neurosurg Psychiatry 1982;45:656–8. 6. Hodson AK, Hurwitz BJ, Albrecht R. Dysautonomia in GuillainBarre´ syndrome with dorsal root ganglioneuropathy, wallerian degeneration, and fatal myocarditis. Ann Neurol 1984;15:88–95.
7. Taubner RW, Salanova V. Acute dysautonomia and polyneuropathy. Arch Neurol 1984;41:1100–1. 8. Takahashi T, Tamura M, Chida K, et al. A case of acute autonomic, sensory and motor neuropathy (AASMN)-less favorable response of the autonomic dysfunctions to IVIg treatment. Rinshou Shinkeigaku 2004;44:643–7 [in Japanese with English abstract]. 9. Borruat FX, Schatz NJ, Glaser JS, Forteza A. Central nervous system involvement in Guillain-Barre´-like syndrome: clinical and magnetic resonance imaging evidence. Eur Neurol 1997;38:129–31. 10. Stoll G, Thomas C, Reiners K, Schober R, Hartung HP. Encephalomyelo-radiculo-ganglionitis presenting as pandysautonomia. Neurology 1991;41:723–6. 11. Maier H, Schmidbauer M, Pfausler B, Schmutzhard E, Budka H. Central nervous system pathology in patients with Guillain-Barre´ syndrome. Brain 1997;120:451–64. 12. Sterns RH, Ocdol H, Scbrier RW, Narins RG. Hyponatremia: pathophysiology, diagnosis, and therapy. In: Maxwell MH, Kleeman RG, Narins RG, editors. Maxwell and Kleeman’s clinical disorders of fluid and electrolyte metabolism. 5th ed. New York: McGraw-Hill; 1994. p. 583–615.
doi:10.1016/j.jocn.2005.12.009
Mycophenolate mofetil – as an adjunctive immunosuppressive therapy in refractory myasthenia gravis: The Singapore experience K.M. Prakash *, P. Ratnagopal, K. Puvanendran, Y.L. Lo National Neuroscience Institute (SGH campus), Department of Neurology, Block 6 Level 8, Singapore General Hospital, Outram Road, Singapore 169608 Received 21 September 2005; accepted 8 December 2005
Abstract We report our experience, using mycophenolate mofetil (MyM) as an adjunctive immunosuppressive therapy in patients with severe, refractory and high dose steroid-dependant myasthenia gravis (MG). Five patients were commenced on MyM in addition to other immunosuppressive therapies. All had significant clinical improvement and no subsequent myasthenic crisis requiring intensive care unit admission. MyM was well tolerated and no serious adverse effects were observed. MyM is an effective adjunctive therapy for the treatment of severe, refractory and steroid-dependant MG in our experience. 2005 Elsevier Ltd. All rights reserved. Keywords: Mycophenolate mofetil; Myasthenia gravis
1. Introduction Immunosuppressive therapies such as corticosteroids, azathioprine and cyclosporine have been commonly used in autoimmune myasthenia gravis (MG). However, variable efficacy, patient tolerance and adverse side effects limit their effectiveness.1,2 Thus, more favorable alterna-
*
Corresponding author. Tel.: +65 63265003; fax: +65 62203321. E-mail address: [email protected] (K.M. Prakash).
tives are needed. Mycophenolate mofetil (MyM) has been successfully used for treating patients with allogeneic transplants and other immune-mediated diseases.3–7 In the past few years there have been several reports from Western countries indicating MyM may be safer, more effective and better tolerated by MG patients.8–10 Currently, there are a number of phase three clinical trials ongoing and at this stage no results have been published. We report our experience using MyM in five patients with myasthenia gravis who had recurrent acute exacerbations and were less responsive to the commonly used immunotherapies.
Case reports / Journal of Clinical Neuroscience 14 (2007) 278–281
2. Case reports
279
commenced more than 5 years earlier, was discontinued. She had no adverse side effects to MyM.
2.1. Case 1 A forty-year-old Chinese woman presented with a 1-month history of bilateral ptosis, mild difficulty swallowing and weakness of her limbs. Examination revealed moderate ptosis, mild orbicularis oris and oculi weakness bilaterally, mild weakness of neck flexor and proximal upper extremities. She had normal speech and eye movements. The Tensilon test, repetitive nerve stimulation and anti-acetylcholine receptor antibodies were positive. She was commenced on pyridostigmine 120 mg three times per day and prednisolone 40 mg every morning. Three months later, she underwent thymectomy surgery. Post-thymectomy, she had recurrent myasthenic crisis requiring intensive care unit (ICU) admissions, plasmaphoresis, and intravenous immunoglobulin therapy, as well as escalating doses of her medication. In addition to pyridostigmine, she was prescribed prednisolone 60 mg per day. Azathioprine 100 mg every morning was added 8 months after disease onset. As a result of prolonged high-dose steroid usage, she developed severe osteopenia. Approximately 2 years after initial presentation, MyM 500 mg three times per day was added. Three weeks after starting MyM, she was weaned off the ventilator. Four weeks later she was ambulating independently and was discharged with good muscle power. She had no further myasthenic crisis. We were able to reduce pyridostigmine to 60 mg three times daily and prednisolone to 4 mg daily and to discontinue azathioprine. Apart from intermittent nausea and diarrhoea in the initial period, she tolerated MyM well since its commencement 14 months ago.
2.2. Case 2 A 29-year-old Chinese woman presented with a 3-week history of double vision and limb weakness. Examination revealed mild ptosis, bilateral partial opthalmoplegic and proximal limb weakness. Her Tensilon test, repetitive nerve stimulation and anti-acetylcholine receptor antibodies were positive. She was commenced on pyridostigmine 60 mg three times daily and prednisolone 40 mg every morning. She also underwent a cervical thymectomy approximately 1 year later. Post-thymectomy, she had recurrent myasthenic crisis requiring intubation and ventilation, immunoglobulin infusion and plasmaphoresis. She also required escalating doses of pyridostigmine up to 120 mg six times a day, prednisolone 60 mg and azathioprine 100 mg both every morning. Over the following 10 years she had multiple similar admissions. Due to prolonged steroid usage she had developed cataracts and significant osteopenia. MyM 500 mg three times daily was added after her last admission approximately 2 years ago. Since then she had no further readmission for acute exacerbations. Her medications have been reduced to pyridostigmine 60 mg three times daily and prednisolone 5 mg every morning. Azathioprine, which was
2.3. Case 3 A 66-year-old Chinese woman presented approximately 2 years ago with a 2-week history of bulbar weakness. Positive repetitive nerve stimulation and single fiber EMG tests as well as elevated anti-acetylcholine receptor antibodies supported the diagnosis of MG. She was admitted to the ICU for ventilatory support. She was given immunoglobulin infusion and plasmaphoresis in addition to high doses of prednisolone (60 mg every morning) and pyridostigmine (120 mg five times a day). She had no CT thorax evidence of thymoma. She was discharged symptomless after a month of in-patient stay. However, she developed myasthenic crisis within 2 months of discharge, requiring mechanical ventilation and immunoglobulin therapy. After 3 weeks, she was commenced on MyM 500 mg three times daily in addition to prednisolone and pyridostigmine. She remained well with no subsequent myasthenic crisis over the last 11 months. The prednisolone was progressively reduced to 20 mg every morning while pyridostigmine was further reduced to 120 mg three times daily.
2.4. Case 4 A 21-year-old Chinese man presented with acute ptosis, double vision and limb weakness. He had strongly positive repetitive nerve stimulation and single fiber electromyographic studies. Anti-acetylcholine receptor antibodies were elevated as well. He was treated with pyridostigmine 120 mg three times daily and prednisolone 40 mg in the morning. He subsequently underwent thymectomy. Postthymectomy he had a total of five admissions within 18 months, three of which required mechanical ventilation. His medications included pyridostigmine 120 mg six times per day, prednisolone 60 mg and azathioprine 100 mg both every morning. As a result of prolonged high-dose steroid usage, he had developed severe cushingoid features. During his last admission approximately 1 year ago, MyM 500 mg three times daily was added. One month later, he noted significant subjective improvement of symptoms and no further myasthenic crisis. We were able to steadily reduce his pyridostigmine to 120 mg three times daily and prednisolone to 5 mg in the morning. Azathioprine, which was commenced just over a year ago, was discontinued. He did not have any major adverse effects with MyM. 2.5. Case 5 A 52-year-old Malay woman presented with a 1-week history of progressive dysphagia, dysarthria, double vision and generalized weakness. She had positive repetitive nerve stimulation and single fiber electromyographic studies, as
280
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well as elevated anti-acetylcholine receptor antibodies. Computed tomography scan of the thorax showed no evidence of thymoma. She was initially treated with pyridostigmine 120 mg four times daily and prednisolone 40 mg every morning. However, as she had no improvement on this treatment, she was given intravenous immunoglobulin and plasmapherisis. She did not require ventilatory support. She was discharged after a 1-month hospital stay. She was prescribed pyridostigmine 120 mg four times daily, prednisolone 60 mg in the morning and MyM 500 mg twice daily. She has been well since then with no myasthenic crisis. During her last clinical review she had minimal ptosis and no evidence of diplopia, ophthalmoplegia, dysarthria or limb weakness. Currently she remains on pyridostigmine 120 mg three times a day, prednisolone 30 mg in the morning and MyM 500 mg twice daily.
3. Discussion Mycophenolate mofetil (MyM) is a potent immunosuppressive agent. It inhibits purine synthesis in activated T and B lymphocytes and selectively inhibits their proliferation while leaving other cell lines intact.3 It is absorbed rapidly and is metabolized into mycophenolic acid, a potent, selective, noncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase.4 It has a strong safety profile and no major organ toxicity or mutagenic effect.4–7 Reports in Western countries showed that MyM appeared to be effective as adjunctive therapy in the treatment of severe, refractory and steroid-dependant myasthenia gravis.8–11 All five of our MG patients had reached a plateau of clinical improvement after receiving high doses of pyridostigmine, steroids and azathioprine. Three of these patients had successful thymectomy performed in the early stages of disease. They were still experiencing severe symptom exacerbation and required high dosages of medication. As such, serious medication-related adverse effects were observed. With the addition of MyM, all five patients had significant clinical improvement. None of them had subsequent myasthenic crisis requiring ICU admission after addition of MyM. Unlike an earlier case report,8 we observed symptomatic improvement beginning 2–4 months after starting MyM. This improvement persisted after the commencement of MyM from approximately 11 months to 2 years. Hence, pyridostigmine could be significantly reduced without causing worsening of symptoms. Similar to previous reports,9–11 our data also suggest a steroid-sparing effect of MyM. All five patients were already on high-dose prednisolone when MyM treatment was begun and were able to decrease the prednisolone dosage without significant clinical worsening. The reduction was crucial in these patients, as some of them had already developed serious long-term steroid-induced adverse effects. This observation may provide the motivation for early commencement of MyM in future cases of refractory MG.
All our patients tolerated MyM well. The serum biochemistry (full blood counts, electrolytes, urea levels and liver function test) that was carried out on all our patients every 3–6 months showed no abnormalities. While the short-term safety profile appeared good with MyM, the long-term adverse effects in our patients remain unknown. We acknowledge that there have been reports of serious side-effects in myasthenia patients treated with MyM.12,13 However, long-term safety profiles of MyM in transplant patients have been encouraging.14 The dosage of MyM used in our patients was 1500 mg per day. Other reports have used between 1000 and 2000 mg per day.15 Although there was no serious short-term adverse effects observed, the optimal dosage remains uncertain in patients of Asian origin. In transplant patients, MyM up to 3500 mg per day has been used with few side effects.16,17 All our patients were receiving other forms of immunosuppression at the time MyM treatment was commenced. Therefore, the potential role of MyM as sole therapy, as reported in an earlier publication,11 remains to be investigated in our patients. Larger, randomized trials are needed to answer this question. To this end, our experience suggests that MyM is a promising alternative to other currently available immunosuppressive drugs for the treatment of refractory MG.
References 1. Hohlfeld R, Michels M, Heininger K, Besinger U, Toyka KV. Azathioprine toxicity during long-term immunosuppression of generalized myasthenia gravis. Neurology 1988;38:258–61. 2. Ciafaloni E, Nikhar NK, Massey JM, Sanders DB. Retrospective analysis of the use of cyclosporine in myasthenia gravis. Neurology 2000;55:448–50. 3. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 1996;10: 77–84. 4. European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. Lancet 1995;345:1321–5. 5. Sollinger HW for the U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995;60:225–32. 6. Behrend M. A review of clinical experience with the novel immunosuppressive drug mycophenolate mofetil in renal transplantation. Clin Nephrol 1996;45:336–41. 7. Allison AC, Eugui EM. Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation. Transplant Proc 1994;26:3205–10. 8. Hauser RA, Malek AR, Rosen R. Successful treatment of a patient with severe refractory myasthenia gravis using mycophenolate mofetil. Neurology 1998;51:912–3. 9. Ciafaloni E, Massey JM, Tucker-Lipscomb B, Sanders DB. Mycophenolate mofetil for myasthenia gravis: an open-label pilot study. Neurology 2001;56:97–9. 10. Meriggioli MN, Rowin J, Richman JG, Leurgans S. Mycophenolate mofetil for myasthenia gravis: a double-blind, placebo-controlled pilot study. Ann NY Acad Sci 2003;998:494–9.
Case reports / Journal of Clinical Neuroscience 14 (2007) 281–283 11. Chaudhry V, Cornblath DR, Griffin JW, O’Brien R, Drachman DB. Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases. Neurology 2001;56:94–6. 12. Vernino S, Salomao DR, Habermann TM, O’Neill BP. Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil. Neurology 2005;65:639–41. 13. Levin N, Mali A, Karussis D. Severe skin reaction related to mycophenolate mofetil for myasthenia gravis. Clin Neuropharmacol 2005;28:152–3.
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14. Haberal M, Karakayali H, Emiroglu R, Basaran O, Moray G, Bilgin N. Malignant tumors after organ transplantation. Artif Organs 2002;26:778–81. 15. Schneider C, Gold R, Reiners K, Toyka KV. Mycophenolate mofetil in the therapy of severe myasthenia gravis. Eur Neurol 2001;46:79–82. 16. Danovitch GM. Mycophenolate mofetil in renal transplant: results from the U.S. randomized trials. Kidney Int 1995;52:S93–6. 17. Sollinger HW. Mycophenolate mofetil. Kidney Int 1995;52:S14–7.
doi:10.1016/j.jocn.2005.12.008
Chronic subdural haematoma associated with nontraumatic CSF rhinorrhea: A management challenge Santosh Isaac Poonnoose *, Raju P. Manjooran, John Mathew, Pranatartiharan Ramachandran Flinders Medical Center, Deparment of Neurosurgery, Flinders Drive, Bedford Park, Adelaide, S.A. 5042 Australia Received 25 October 2005; accepted 27 November 2005
Abstract We report an unusual case of chronic subdural haematoma (CSH) associated with cerebrospinal fluid (CSF) rhinorrhoea emphasizing the importance of managing both conditions simultaneously. A 59- year-old man presented with watery discharge from the right nostril, of 2 months duration. MRI of the brain showed a CSH in the left fronto-parietal region with significant mass effect. There was an arachnoidocoele with a defect in the planum sphenoidale. He first underwent a burr hole evacuation of the CSH following which the CSF rhinorrhea did not subside, even with bed rest. Transnasal endoscopic closure of the CSF dural fistula was done. On the first post-operative day, he was disoriented and a CT scan showed a recollection of the subdural haematoma that required repeat evacuation. The patient was asymptomatic at discharge. To our knowledge this is the first reported case of CSF rhinorrhoea associated with CSH. Simultaneous closure of the CSF dural fistula at the time of evacuation of a coexisting CSH would be the optimal management. 2006 Elsevier Ltd. All rights reserved. Keywords: CSF rhinorrhea; Chronic subdural haematoma
1. Introduction Cerebrospinal fluid (CSF) rhinorrhea involves a breakdown of all barriers that separate the subarachnoid space from the nasal cavity or paranasal sinuses. This may be traumatic or spontaneous. We document a case of CSF rhinorrhea associated with a chronic subdural haematoma, an entity that has not been previously reported, and discuss its management. 2. Case report A 59-year-old man presented with a history of watery discharge from the right nostril of 2 months duration. There was no history of trauma or symptoms of raised intracranial pressure (ICP) preceding the onset of the rhinorrhea. On *
Corresponding author. Tel.: +61 08 82044355; fax: +61 08 82045116. E-mail address: s_poonnoose@rediffmail.com (S.I. Poonnoose).
examination he had a right supranuclear facial paresis and mild right-sided pyramidal signs. The fundi were normal. The rhinorrhea worsened when he leaned forward. MRI of the head showed a left fronto-parietal chronic subdural haematoma (CSH) of 2.5 cm thickness, with significant mass effect. There was also evidence of fluid within the sphenoid sinus that appeared to be in communication with the subarachnoid space through a defect in the right side of the planum sphenoidale (Fig. 1). The cribriform plate region appeared normal. The CSH was evacuated under local anesthesia through two burr holes, one in the frontal and the other in the parietal region. On making cruciate dural incisions, 40–50 mL of altered blood was drained under high pressure. Postoperatively he was kept on bed-rest for 2 weeks, despite which the CSF leak continued. A postoperative CT was not done, to rule out a possible recollection of the subdural haematoma. A transnasal endoscopic closure of the CSF dural fistula was done. The cranial base defect was seen on the right
Case reports / Journal of Clinical Neuroscience 14 (2007) 278–281
References 1. Yokota T, Hayashi M, Hirashima F, Mitani M, Tanabe H, Tsukagoshi H. Dysautonomia with acute sensory motor neuropathy. Arch Neurol 1994;51:1022–31. 2. Adachi H, Mukai E, Okuda S, Kawada T. A severe case of acute autonomic and sensory neuropathy. Rinshou Shinkeigaku 1998;38:663–8 [in Japanese with English abstract]. 3. Okada F. Psychiatric aspects of acute pandysautonomia. Eur Arch Psychiatry Clin Neurosci 1990;240:134–5. 4. Nakagawa T, Kumamoto T, Watanabe S, Uchino M, Araki S. A case of acute autonomic, sensory and motor neuropathy. Rinshou Shinkeigaku 1988;28:260–7 [in Japanese with English abstract]. 5. Fujii N, Tabira T, Shibasaki H, Kuroiwa Y, Ohnishi A, Nagaki J. Acute autonomic and sensory neuropathy associated with elevated Epstein-Barr virus antibody titer. J Neurol Neurosurg Psychiatry 1982;45:656–8. 6. Hodson AK, Hurwitz BJ, Albrecht R. Dysautonomia in GuillainBarre´ syndrome with dorsal root ganglioneuropathy, wallerian degeneration, and fatal myocarditis. Ann Neurol 1984;15:88–95.
7. Taubner RW, Salanova V. Acute dysautonomia and polyneuropathy. Arch Neurol 1984;41:1100–1. 8. Takahashi T, Tamura M, Chida K, et al. A case of acute autonomic, sensory and motor neuropathy (AASMN)-less favorable response of the autonomic dysfunctions to IVIg treatment. Rinshou Shinkeigaku 2004;44:643–7 [in Japanese with English abstract]. 9. Borruat FX, Schatz NJ, Glaser JS, Forteza A. Central nervous system involvement in Guillain-Barre´-like syndrome: clinical and magnetic resonance imaging evidence. Eur Neurol 1997;38:129–31. 10. Stoll G, Thomas C, Reiners K, Schober R, Hartung HP. Encephalomyelo-radiculo-ganglionitis presenting as pandysautonomia. Neurology 1991;41:723–6. 11. Maier H, Schmidbauer M, Pfausler B, Schmutzhard E, Budka H. Central nervous system pathology in patients with Guillain-Barre´ syndrome. Brain 1997;120:451–64. 12. Sterns RH, Ocdol H, Scbrier RW, Narins RG. Hyponatremia: pathophysiology, diagnosis, and therapy. In: Maxwell MH, Kleeman RG, Narins RG, editors. Maxwell and Kleeman’s clinical disorders of fluid and electrolyte metabolism. 5th ed. New York: McGraw-Hill; 1994. p. 583–615.
doi:10.1016/j.jocn.2005.12.009
Mycophenolate mofetil – as an adjunctive immunosuppressive therapy in refractory myasthenia gravis: The Singapore experience K.M. Prakash *, P. Ratnagopal, K. Puvanendran, Y.L. Lo National Neuroscience Institute (SGH campus), Department of Neurology, Block 6 Level 8, Singapore General Hospital, Outram Road, Singapore 169608 Received 21 September 2005; accepted 8 December 2005
Abstract We report our experience, using mycophenolate mofetil (MyM) as an adjunctive immunosuppressive therapy in patients with severe, refractory and high dose steroid-dependant myasthenia gravis (MG). Five patients were commenced on MyM in addition to other immunosuppressive therapies. All had significant clinical improvement and no subsequent myasthenic crisis requiring intensive care unit admission. MyM was well tolerated and no serious adverse effects were observed. MyM is an effective adjunctive therapy for the treatment of severe, refractory and steroid-dependant MG in our experience. 2005 Elsevier Ltd. All rights reserved. Keywords: Mycophenolate mofetil; Myasthenia gravis
1. Introduction Immunosuppressive therapies such as corticosteroids, azathioprine and cyclosporine have been commonly used in autoimmune myasthenia gravis (MG). However, variable efficacy, patient tolerance and adverse side effects limit their effectiveness.1,2 Thus, more favorable alterna-
*
Corresponding author. Tel.: +65 63265003; fax: +65 62203321. E-mail address: [email protected] (K.M. Prakash).
tives are needed. Mycophenolate mofetil (MyM) has been successfully used for treating patients with allogeneic transplants and other immune-mediated diseases.3–7 In the past few years there have been several reports from Western countries indicating MyM may be safer, more effective and better tolerated by MG patients.8–10 Currently, there are a number of phase three clinical trials ongoing and at this stage no results have been published. We report our experience using MyM in five patients with myasthenia gravis who had recurrent acute exacerbations and were less responsive to the commonly used immunotherapies.
Case reports / Journal of Clinical Neuroscience 14 (2007) 278–281
2. Case reports
279
commenced more than 5 years earlier, was discontinued. She had no adverse side effects to MyM.
2.1. Case 1 A forty-year-old Chinese woman presented with a 1-month history of bilateral ptosis, mild difficulty swallowing and weakness of her limbs. Examination revealed moderate ptosis, mild orbicularis oris and oculi weakness bilaterally, mild weakness of neck flexor and proximal upper extremities. She had normal speech and eye movements. The Tensilon test, repetitive nerve stimulation and anti-acetylcholine receptor antibodies were positive. She was commenced on pyridostigmine 120 mg three times per day and prednisolone 40 mg every morning. Three months later, she underwent thymectomy surgery. Post-thymectomy, she had recurrent myasthenic crisis requiring intensive care unit (ICU) admissions, plasmaphoresis, and intravenous immunoglobulin therapy, as well as escalating doses of her medication. In addition to pyridostigmine, she was prescribed prednisolone 60 mg per day. Azathioprine 100 mg every morning was added 8 months after disease onset. As a result of prolonged high-dose steroid usage, she developed severe osteopenia. Approximately 2 years after initial presentation, MyM 500 mg three times per day was added. Three weeks after starting MyM, she was weaned off the ventilator. Four weeks later she was ambulating independently and was discharged with good muscle power. She had no further myasthenic crisis. We were able to reduce pyridostigmine to 60 mg three times daily and prednisolone to 4 mg daily and to discontinue azathioprine. Apart from intermittent nausea and diarrhoea in the initial period, she tolerated MyM well since its commencement 14 months ago.
2.2. Case 2 A 29-year-old Chinese woman presented with a 3-week history of double vision and limb weakness. Examination revealed mild ptosis, bilateral partial opthalmoplegic and proximal limb weakness. Her Tensilon test, repetitive nerve stimulation and anti-acetylcholine receptor antibodies were positive. She was commenced on pyridostigmine 60 mg three times daily and prednisolone 40 mg every morning. She also underwent a cervical thymectomy approximately 1 year later. Post-thymectomy, she had recurrent myasthenic crisis requiring intubation and ventilation, immunoglobulin infusion and plasmaphoresis. She also required escalating doses of pyridostigmine up to 120 mg six times a day, prednisolone 60 mg and azathioprine 100 mg both every morning. Over the following 10 years she had multiple similar admissions. Due to prolonged steroid usage she had developed cataracts and significant osteopenia. MyM 500 mg three times daily was added after her last admission approximately 2 years ago. Since then she had no further readmission for acute exacerbations. Her medications have been reduced to pyridostigmine 60 mg three times daily and prednisolone 5 mg every morning. Azathioprine, which was
2.3. Case 3 A 66-year-old Chinese woman presented approximately 2 years ago with a 2-week history of bulbar weakness. Positive repetitive nerve stimulation and single fiber EMG tests as well as elevated anti-acetylcholine receptor antibodies supported the diagnosis of MG. She was admitted to the ICU for ventilatory support. She was given immunoglobulin infusion and plasmaphoresis in addition to high doses of prednisolone (60 mg every morning) and pyridostigmine (120 mg five times a day). She had no CT thorax evidence of thymoma. She was discharged symptomless after a month of in-patient stay. However, she developed myasthenic crisis within 2 months of discharge, requiring mechanical ventilation and immunoglobulin therapy. After 3 weeks, she was commenced on MyM 500 mg three times daily in addition to prednisolone and pyridostigmine. She remained well with no subsequent myasthenic crisis over the last 11 months. The prednisolone was progressively reduced to 20 mg every morning while pyridostigmine was further reduced to 120 mg three times daily.
2.4. Case 4 A 21-year-old Chinese man presented with acute ptosis, double vision and limb weakness. He had strongly positive repetitive nerve stimulation and single fiber electromyographic studies. Anti-acetylcholine receptor antibodies were elevated as well. He was treated with pyridostigmine 120 mg three times daily and prednisolone 40 mg in the morning. He subsequently underwent thymectomy. Postthymectomy he had a total of five admissions within 18 months, three of which required mechanical ventilation. His medications included pyridostigmine 120 mg six times per day, prednisolone 60 mg and azathioprine 100 mg both every morning. As a result of prolonged high-dose steroid usage, he had developed severe cushingoid features. During his last admission approximately 1 year ago, MyM 500 mg three times daily was added. One month later, he noted significant subjective improvement of symptoms and no further myasthenic crisis. We were able to steadily reduce his pyridostigmine to 120 mg three times daily and prednisolone to 5 mg in the morning. Azathioprine, which was commenced just over a year ago, was discontinued. He did not have any major adverse effects with MyM. 2.5. Case 5 A 52-year-old Malay woman presented with a 1-week history of progressive dysphagia, dysarthria, double vision and generalized weakness. She had positive repetitive nerve stimulation and single fiber electromyographic studies, as
280
Case reports / Journal of Clinical Neuroscience 14 (2007) 278–281
well as elevated anti-acetylcholine receptor antibodies. Computed tomography scan of the thorax showed no evidence of thymoma. She was initially treated with pyridostigmine 120 mg four times daily and prednisolone 40 mg every morning. However, as she had no improvement on this treatment, she was given intravenous immunoglobulin and plasmapherisis. She did not require ventilatory support. She was discharged after a 1-month hospital stay. She was prescribed pyridostigmine 120 mg four times daily, prednisolone 60 mg in the morning and MyM 500 mg twice daily. She has been well since then with no myasthenic crisis. During her last clinical review she had minimal ptosis and no evidence of diplopia, ophthalmoplegia, dysarthria or limb weakness. Currently she remains on pyridostigmine 120 mg three times a day, prednisolone 30 mg in the morning and MyM 500 mg twice daily.
3. Discussion Mycophenolate mofetil (MyM) is a potent immunosuppressive agent. It inhibits purine synthesis in activated T and B lymphocytes and selectively inhibits their proliferation while leaving other cell lines intact.3 It is absorbed rapidly and is metabolized into mycophenolic acid, a potent, selective, noncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase.4 It has a strong safety profile and no major organ toxicity or mutagenic effect.4–7 Reports in Western countries showed that MyM appeared to be effective as adjunctive therapy in the treatment of severe, refractory and steroid-dependant myasthenia gravis.8–11 All five of our MG patients had reached a plateau of clinical improvement after receiving high doses of pyridostigmine, steroids and azathioprine. Three of these patients had successful thymectomy performed in the early stages of disease. They were still experiencing severe symptom exacerbation and required high dosages of medication. As such, serious medication-related adverse effects were observed. With the addition of MyM, all five patients had significant clinical improvement. None of them had subsequent myasthenic crisis requiring ICU admission after addition of MyM. Unlike an earlier case report,8 we observed symptomatic improvement beginning 2–4 months after starting MyM. This improvement persisted after the commencement of MyM from approximately 11 months to 2 years. Hence, pyridostigmine could be significantly reduced without causing worsening of symptoms. Similar to previous reports,9–11 our data also suggest a steroid-sparing effect of MyM. All five patients were already on high-dose prednisolone when MyM treatment was begun and were able to decrease the prednisolone dosage without significant clinical worsening. The reduction was crucial in these patients, as some of them had already developed serious long-term steroid-induced adverse effects. This observation may provide the motivation for early commencement of MyM in future cases of refractory MG.
All our patients tolerated MyM well. The serum biochemistry (full blood counts, electrolytes, urea levels and liver function test) that was carried out on all our patients every 3–6 months showed no abnormalities. While the short-term safety profile appeared good with MyM, the long-term adverse effects in our patients remain unknown. We acknowledge that there have been reports of serious side-effects in myasthenia patients treated with MyM.12,13 However, long-term safety profiles of MyM in transplant patients have been encouraging.14 The dosage of MyM used in our patients was 1500 mg per day. Other reports have used between 1000 and 2000 mg per day.15 Although there was no serious short-term adverse effects observed, the optimal dosage remains uncertain in patients of Asian origin. In transplant patients, MyM up to 3500 mg per day has been used with few side effects.16,17 All our patients were receiving other forms of immunosuppression at the time MyM treatment was commenced. Therefore, the potential role of MyM as sole therapy, as reported in an earlier publication,11 remains to be investigated in our patients. Larger, randomized trials are needed to answer this question. To this end, our experience suggests that MyM is a promising alternative to other currently available immunosuppressive drugs for the treatment of refractory MG.
References 1. Hohlfeld R, Michels M, Heininger K, Besinger U, Toyka KV. Azathioprine toxicity during long-term immunosuppression of generalized myasthenia gravis. Neurology 1988;38:258–61. 2. Ciafaloni E, Nikhar NK, Massey JM, Sanders DB. Retrospective analysis of the use of cyclosporine in myasthenia gravis. Neurology 2000;55:448–50. 3. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 1996;10: 77–84. 4. European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. Lancet 1995;345:1321–5. 5. Sollinger HW for the U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995;60:225–32. 6. Behrend M. A review of clinical experience with the novel immunosuppressive drug mycophenolate mofetil in renal transplantation. Clin Nephrol 1996;45:336–41. 7. Allison AC, Eugui EM. Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation. Transplant Proc 1994;26:3205–10. 8. Hauser RA, Malek AR, Rosen R. Successful treatment of a patient with severe refractory myasthenia gravis using mycophenolate mofetil. Neurology 1998;51:912–3. 9. Ciafaloni E, Massey JM, Tucker-Lipscomb B, Sanders DB. Mycophenolate mofetil for myasthenia gravis: an open-label pilot study. Neurology 2001;56:97–9. 10. Meriggioli MN, Rowin J, Richman JG, Leurgans S. Mycophenolate mofetil for myasthenia gravis: a double-blind, placebo-controlled pilot study. Ann NY Acad Sci 2003;998:494–9.
Case reports / Journal of Clinical Neuroscience 14 (2007) 281–283 11. Chaudhry V, Cornblath DR, Griffin JW, O’Brien R, Drachman DB. Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases. Neurology 2001;56:94–6. 12. Vernino S, Salomao DR, Habermann TM, O’Neill BP. Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil. Neurology 2005;65:639–41. 13. Levin N, Mali A, Karussis D. Severe skin reaction related to mycophenolate mofetil for myasthenia gravis. Clin Neuropharmacol 2005;28:152–3.
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doi:10.1016/j.jocn.2005.12.008
Chronic subdural haematoma associated with nontraumatic CSF rhinorrhea: A management challenge Santosh Isaac Poonnoose *, Raju P. Manjooran, John Mathew, Pranatartiharan Ramachandran Flinders Medical Center, Deparment of Neurosurgery, Flinders Drive, Bedford Park, Adelaide, S.A. 5042 Australia Received 25 October 2005; accepted 27 November 2005
Abstract We report an unusual case of chronic subdural haematoma (CSH) associated with cerebrospinal fluid (CSF) rhinorrhoea emphasizing the importance of managing both conditions simultaneously. A 59- year-old man presented with watery discharge from the right nostril, of 2 months duration. MRI of the brain showed a CSH in the left fronto-parietal region with significant mass effect. There was an arachnoidocoele with a defect in the planum sphenoidale. He first underwent a burr hole evacuation of the CSH following which the CSF rhinorrhea did not subside, even with bed rest. Transnasal endoscopic closure of the CSF dural fistula was done. On the first post-operative day, he was disoriented and a CT scan showed a recollection of the subdural haematoma that required repeat evacuation. The patient was asymptomatic at discharge. To our knowledge this is the first reported case of CSF rhinorrhoea associated with CSH. Simultaneous closure of the CSF dural fistula at the time of evacuation of a coexisting CSH would be the optimal management. 2006 Elsevier Ltd. All rights reserved. Keywords: CSF rhinorrhea; Chronic subdural haematoma
1. Introduction Cerebrospinal fluid (CSF) rhinorrhea involves a breakdown of all barriers that separate the subarachnoid space from the nasal cavity or paranasal sinuses. This may be traumatic or spontaneous. We document a case of CSF rhinorrhea associated with a chronic subdural haematoma, an entity that has not been previously reported, and discuss its management. 2. Case report A 59-year-old man presented with a history of watery discharge from the right nostril of 2 months duration. There was no history of trauma or symptoms of raised intracranial pressure (ICP) preceding the onset of the rhinorrhea. On *
Corresponding author. Tel.: +61 08 82044355; fax: +61 08 82045116. E-mail address: s_poonnoose@rediffmail.com (S.I. Poonnoose).
examination he had a right supranuclear facial paresis and mild right-sided pyramidal signs. The fundi were normal. The rhinorrhea worsened when he leaned forward. MRI of the head showed a left fronto-parietal chronic subdural haematoma (CSH) of 2.5 cm thickness, with significant mass effect. There was also evidence of fluid within the sphenoid sinus that appeared to be in communication with the subarachnoid space through a defect in the right side of the planum sphenoidale (Fig. 1). The cribriform plate region appeared normal. The CSH was evacuated under local anesthesia through two burr holes, one in the frontal and the other in the parietal region. On making cruciate dural incisions, 40–50 mL of altered blood was drained under high pressure. Postoperatively he was kept on bed-rest for 2 weeks, despite which the CSF leak continued. A postoperative CT was not done, to rule out a possible recollection of the subdural haematoma. A transnasal endoscopic closure of the CSF dural fistula was done. The cranial base defect was seen on the right