Original Article
Fulminant variants of multiple sclerosis: local experience at Shifa International Hospital, Islamabad, Pakistan Arsalan Ahmad, Nadia Mehboob, Ismail Abdul Latif Khatri, Maimoona Siddiqui, Javeria Khizar, Maryam Jameel Division of Neurology, Shifa International Hospital, Islamabad, Pakistan, Department of Medicine, King Abdul Aziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia and Armed Forces Institute of Cardiology, Rawalpindi, Pakistan Objective: To report a series of patients with fulminant variants of multiple sclerosis (MS) based on their clinical and radiological features Methodology: This retrospective study consists of series of four patients with fulminant variants of MS seen between January 2008 and February 2011 at Shifa International Hospital, Islamabad, Pakistan. Results: Out of Four patients, three were females, with mean age of 27 (range 13-40) years. Onset was acute with significant progression over 2 weeks in all cases. Presenting symptoms were hemiparesis and speech difficulty in all patients, 3 had visual impairment, and 2 had headache. CSF pleocytosis and raised CSF protein was seen in 3 patients. Visual evoked potentials were abnormal in one patient. Based on the characteristic MRI findings, 3 patients were diagnosed as Balo's
INTRODUCTION 1 Multiple sclerosis (MS) was first described in 1868. This is a chronic inflammatory and demyelinating disease of the central nervous system predominantly 2 involving the white matter. The diagnosis encompasses a broad spectrum of disorders which might be monophasic, recurrent or progressive and can be identified on the basis of clinico-radiological findings.3 There has been an increase in the prevalence of MS globally with the estimated prevalence of 30 per 100,000.4 The prevalence of 5 MS varies considerably in Asian countries. There are no epidemiological studies available from Pakistan, however, in India the reported prevelance
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concentric sclerosis and one patient with Marburg's variant of MS. All patients were initially treated with intravenous methylprednisolone followed by immunomodulatory therapy. Two patients received intravenous immunoglobulins (IVIG) and mitoxantrone, one received IVIG only and one received mitoxantrone only. On follow up, all 4 patients had shown marked improvement with independence in activities of daily living. Conclusion: Aggressive treatment with IVIG and mitoxantrone resulted in significant improvement in this small case series. Early and aggressive immunosuppression should be considered in patients with fulminant variants of MS. (Rawal Med J 2013;38: 26-31). Key words: Multiple sclerosis, Balo's concentric sclerosis, Marburg's variant.
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is 3 per 100,000. In addition to prototypic MS, there are some other acute and fulminant forms like Marburg variant of acute MS, Balo's concentric sclerosis and neuromyelitis optica (Devic's 3 Disease). Fulminant variants are the most malignant forms of MS which have high mortality 7 and morbidity. This report describes a series of four patients who were diagnosed as fulminant variants of multiple sclerosis based on their clinical and radiological features. The patients were seen between January 2008 and February 2011 at Shifa International Hospital, Islamabad. The demographic and baseline characteristics are summarized in Table 1.
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Fulminant variants of multiple sclerosis Table1: Demographic and baseline characteristics of the patients.
CASE PRESENTATIONS Case 1: A 33 years old man, hypertensive, who had renal transplant 7 years ago and had recently started treatment for pulmonary tuberculosis, developed new onset seizures. He initially refused neuroimaging and was treated with antiepileptic medications alone. However, he developed recurrent seizures with left hemiparesis. CT scan and MRI of brain showed large areas of abnormal signals involving bilateral deep paraventricular and subcortical white matter (Figure 1). Cerebrospinal fluid studies were normal. He refused brain biopsy. 27
Figure 1. MRI FLAIR of patient 1, as the disease evolved.
Day 1
Day 10
Day 14
8 weeks post treatment
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Fulminant variants of multiple sclerosis
Expanded Disability Status Score (EDSS) on admission was 6.0. While in hospital, he developed status epilepticus and was intubated. He was started on anesthetic doses of anticonvulsants and intravenous methylprednisolone. He was successfully extubated on day 3. The left hemiparesis resolved. A follow up MRI showed interval resolution of enhancement. He was discharged home on EDSS of 1.0. Six days after completion of IV methylprednisolone he developed headache, dizziness, diplopia, sleepiness, followed by blindness and subsequently decreased level of consciousness. EDSS was 4.5 at that time. Repeat MRI scan showed extensive progression of the demyelinating illness in the posterior regions of brain. A repeat spinal tap showed elevation of proteins to 121mg/dL. He was diagnosed as Marburg's variant of MS and was given intravenous immunoglobulin (IVIG) 0.4gm/kg/day for 5 days. He became fully alert on day 6 and was discharged home in a stable condition while he was ambulatory with the EDSS of 2.0. He came for follow up after 2 weeks and was started on mitoxantrone (12 mg/m2 body surface area per cycle). Now he has completed 6 cycles of mitoxantrone with normal echo. He is independent in the activities of daily living with an EDSS of 1.0 till his last follow up. Case 2: A 41 year old woman presented with speech difficulty, left hemiparesis, diplopia and altered sensorium for 2 weeks. MRI brain showed multiple hyperintense lesions in periventricular and subcortical white matter suggestive of demyelinating process. CSF examination showed WBC count of 12 cells/uL with lymphocytic pleocytosis and slightly raised protein. She was given intravenous methylprednisolone 1 gram daily for 3 days. She was shifted to our hospital due to disease progression. EDSS at the admission was 7.5. Her repeat MRI showed multiple large subcortical lesions with surrounding concentric rings. Based on fulminant course of disease and MRI findings she was diagnosed as a case of Balo's concentric sclerosis. She was treated with intravenous methylprednisolone 1 gram for 5 days initially and 2 later started on mitoxantrone (12 mg/m body surface area per cycle). She was discharged home on EDSS of 6.5. She came for follow up regularly and now has completed 6 cycles of mitoxantrone.
During recovery, she had psychiatric symptoms including paranoia, delirium, depression and pseudobulbar effect. Her repeat MRI showed interval decrease in white matter disease. She is now independent in activities of daily living and under treatment of psychiatrist for impulse control disorder. EDSS at last follow up was1.5. Case 3: A 25 years old woman presented with stammering of speech for 2 weeks with subsequent worsening of speech to the point that she was mute at the time of presentation. She had gradually become incontinent and constipated. She walked with an unsteady gait and did not follow commands. Her EDSS at that time was 5.0. MRI brain showed multiple large white matter lesions, which were rounded with surrounding halo and some enhancement in few lesions. Spinal tap showed WBC count of 3 cells/uL with 43.5 mg/dL protein and 65 mg/dL glucose. She was diagnosed as Balo's concentric sclerosis and was treated with intravenous methylprednisolone 1 gm daily for 5 days. Then she was given IVIG 0.4 g/kg/day for 5 days. With 3rd dose of IVIG her symptoms started to improve. A week later she regained her speech, bowel and bladder control and ambulation. Till last follow up she was asymptomatic with the EDSS of 0. Case 4: A 13 year old female with no known comorbids presented with weakness of right half of body, speech difficulty and irritable behavior for 1 week. She had an episode of sudden loss of vision in both eyes preceded by severe headache 15 days back. EDSS on admission was 6.0. Visual evoked potentials (VEP) revealed bilateral optic pathway dysfunction. MRI brain with contrast showed concentric multiple white matter lesions with a halo around them, but no significant contrast enhancement (Figure 2). Figure2. T2 weighted MRI of patient 4, axial (a), and coronal (b) images showing high signal intensity white matter lesions with surrounding halo
(a)
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(b)
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Fulminant variants of multiple sclerosis
Oligoclonal bands were negative on CSF electrophoresis. She was treated with intravenous methylprednisolone 1gm daily for five days. Her weakness, speech and vision improved significantly and she was discharged with EDSS of 6.0. Patient came for follow up was started on mitroxantrone (12 2 mg/m body surface area). Now she has completed 7 cycles of mitoxantrone with regular cardiac monitoring. She is now mobilizing without support and is independent in activities of daily living. EDSS on her last follow up visit was 2.5. DISCUSSION Multiple sclerosis is a frequently seen demyelinating disorder which has variable and unpredictable course.8 The earlier the patient suffers from this disease better is the prognosis. Patients who experience first attack after the age of 50 years have rapid progression of disability and severe disease.9 Fulminant multiple sclerosis is the acute and malignant form of MS which usually leads to death or severe disability in few weeks.7 Mean age in our patients was 27 years with female to male ratio of 3:1. The mean duration of follow up in our patients is 2.2 years. Onset was acute with significant progression of disease with in 2 weeks in all 4 cases. Motor weakness and speech difficulty were the commonest symptoms present in all 4 patients followed by visual symptoms seen in 3 out of 4 patients. The prevalence of epilepsy in MS patients has been studied for long and there is evidence that MS patients are at a greater risk of developing seizures as compared to general population.10 In our series, 1 out of 4 patients had seizures at the onset of disease. Mean EDSS at presentation was 6. Diagnosis of MS is usually clinical and depends on thorough history and examination. MRI is the most sensitive, specific diagnostic modality and is the imaging technique of choice for diagnosing these disorders.11 CSF analysis and VEP are the supportive tests used to compliment the diagnosis.8,11 MRI was done in all 4 patients and helped us to diagnose fulminating forms of MS. CSF pleocytosis and raised CSF proteins were seen in 3 patients. VEP was abnormal in one patient. All of our patients were initially treated with I/V 29
steroids followed by immunomodulatory therapy. Two patients received IVIG and mitoxantrone, one received IVIG only and one received mitoxantrone only. All four are independent in activities of daily living and mean EDSS was 1.25 at last follow up. Marburg's disease is an acute and fulminating demyelinating disorder that has a very malignant and rapid course and can cause severe disability or 12-15 mortality in weeks to months. Pathologically, the lesions are similar to MS but have more extensive areas of demyelination and lesions are more destructive.12,14 No consistently successful treatment for Marburg variant MS has been described. Steroids and different immunomodulatory treatments have been tried with success in some patients and failure in others.13,15 However, our patient was successfully treated with combination of steroids, IVIG and mitoxantrone and is independent in ADL. As Marburg is a rare variant of MS high index of suspicion should always be kept in mind when the patient presents with rapidly progressing demyelinating disease and symptoms similar to MS. Balo's concentric sclerosis (BCS) is also a rare and fulminant variant of MS. It usually has a severe and rapidly progressive course. Pathologically, BCS has concentric rings of demyelination alternating with myelination in the white matter. Initially it was thought to be a fatal disease but with the advancement in diagnostic imaging and immunomodulatory treatment it is being diagnosed earlier and is now considered to be treatable. Steroids have been used successfully in such patients and successful outcomes were seen in patients who were treated with steroids and immunomodulatory therapy.16-18 All of our patients were diagnosed as BCS based on characteristic MRI findings, received steroids and two received immunomodulatory agents and all responded well to the treatment. Intravenous steroids is an established treatment for MS relapses as it has shown to accelerate the 19,20 recovery, however, they do not prevent future relapses. IVIG is a relatively safe and well tolerated 21 immunomodulatory agent. They cause reduction of relapse rate and improvement in disability scores 22,23 which has been proven by the randomized trials.
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Three out of our four patients received IVIG and aggressive treatment with IVIG resulted in significant improvement in our small case series. Mitoxantrone is an approved treatment for secondary progressive and aggressive multiple sclerosis since October 2000. It has been shown to be beneficial in reducing the relapse rates and slowing the disability progression.22 The standard 2 dose is 12mg/m in infusion every 3 months for a maximum of 140 mg/m2 which is convenient and cost effective. Evidence shows that mitoxantrone could be a first-line treatment for malignant forms of MS and three of our patients responded very well to mitoxantrone. The potential serious side effects of mitoxantrone should be carefully considered against the potential benefits on every single MS 24 patient. To date none of our patients have developed any serious adverse effects. CONCLUSION The key to successful management of fulminant variants of MS is early diagnosis and early initiation of treatment. Aggressive treatment with IVIG and mitoxantrone in our series resulted in significant improvement. We conclude that early and aggressive immunosuppression should be considered in patients with fulminant variants of MS. Author Contributions: Conception and design: Drs Arsalan and Ismail Collection and assembly of data: Drs Arsalan Nadia, Maimoona, Javeria, Maryam Analysis and interpretation of the data: Drs Arsalan, Ismail, Nadia, Drafting of the article: Drs Nadia, Arsalan, Javeria, Maryam Critical revision of the article for important intellectual content: Drs Arsalan, Ismail, Maimoona Final approval and guarantor of the article: Dr Arsalan Conflict of interest: None declared. The contents of this article were presented as a poster in the XXth World Congress of Neurology in November 2011 in Marrakesh, Morocco Corresponding author email:
[email protected] Rec Date: Sep 07, 2012 Accept Date: Nov 21, 2012
2.
30
4.
5.
6. 7.
8. 9. 10.
11.
12.
13.
14.
15.
16.
REFERENCES 1.
3.
Chen SJ, Wang YL, Fan HC, Lo WT, Wang CC, Sytwu HK. Current status of the immunomodulation and immunomediated therapeutic strategies for multiple sclerosis. Clin Dev Immunol. 2012;2012:970789. Epub 2011 Dec 6. Zivadinov R, Pirko I. Advances in understanding gray matter pathology in multiple sclerosis: are we ready to
17.
18.
redefine disease pathogenesis? BMC Neurol. 2012 Mar 6;12:9. Hu W, Lucchinetti CF. The pathological spectrum of CNS inflammatory demyelinating diseases. Semin Immunopathol. 2009 Nov;31(4):439-53. Epub 2009 Sep 25. González-Andrade F, Alcaraz-Alvarez JL. Diseasemodifying therapies in relapsing-remitting multiple sclerosis. Neuropsychiatr Dis Treat. 2010 Sep 7;6:36573. Wasay M, Ali S, Khatri IA, Hassan A, Asif M, Zakiullah N, Ahmed A, Malik A, Khealani B, Haq A, Fredrikson S. Multiple sclerosis in Pakistan. Mult Scler. 2007 Jun;13(5):668-9. Epub 2007 Feb 9. Pandit L, Murthy JM. Treatment of multiple sclerosis. Ann Indian Acad Neurol. 2011 Jul;14(Suppl 1):S65-9. Rohani M, Ghourchian S. Fulminant multiple sclerosis (MS). Neurol Sci. 2011 Oct; 32(5):953-7. Epub 2011 Aug 24 Goldenberg MM. Multiple sclerosis review. P T. 2012 Mar; 37(3):175-84. Opara JA, Jaracz K, Brola W. Quality of life in multiple sclerosis. J Med Life. 2010 Oct-Dec;3(4):352-8. Viveiros CD, Alvarenga RM. Prevalence of epilepsy in a case series of multiple sclerosis patients. Arq Neuropsiquiatr. 2010 Oct;68(5):731-6. Hilas O, Patel PN, Lam S. Disease modifying agents for multiple sclerosis. Open Neurol J. 2010 May 26; 4:1524. Elenein RG, Sharer LR, Cook SD, Pachner AR, Michaels J, Hillen ME. A second case of Marburg's variant of multiple sclerosis with vasculitis and extensive demyelination. Mult Scler. 2011 Dec;17(12):1531-8. Nozaki K, Abou-Fayssal N. High dose cyclophosphamide treatment in Marburg variant multiple sclerosis A case report. J Neurol Sci. 2010 Sep 15;296(1-2):121-3. Walid MS, Sanoufa M. The diagnosis of Marburg disease is course-dependent. Ger Med Sci. 2010 Mar 2;8:Doc06. Jeffery DR, Lefkowitz DS, Crittenden JP. Treatment of Marburg variant multiple sclerosis with mitoxantrone. J Neuroimaging. 2004 Jan;14(1):58-62. Badar F, Azfar SF, Ahmad I, Kirmani S, Rashid M. Balo's concentric sclerosis involving bilateral thalami. Neurol India. 2011 Jul-Aug;59(4):597-600. Li Y, Xie P, Fan X, Tang H. Balò's concentric sclerosis presenting with benign clinical course and multiple sclerosis-like lesions on magnetic resonance images. Neurol India. 2009 Jan-Feb;57(1):66-8. Lanciano NJ, Lyu DS, Hoegerl C. High-dose steroid treatment in a patient with Balò disease diagnosed by
Rawal Medical Journal: Vol. 38. No. 1, January-March 2013
Fulminant variants of multiple sclerosis
19.
20.
31
means of magnetic resonance imaging. J Am Osteopath Assoc. 2011 Mar; 111(3):170-2. Kalanie H, Harandi AA, Alidaei S, Heidari D, Shahbeigi S, Ghorbani M. Venous thrombosis in multiple sclerosis patients after high-dose intravenous methylprednisolone: the preventive effect of enoxaparin. Thrombosis. 2011;2011: 785459. Epub 2011 Dec 25. Humm AM, Z'Graggen WJ, Bühler R, Magistris MR, Rösler KM. Quantification of central motor conduction deficits in multiple sclerosis patients before and after treatment of acute exacerbation by methylprednisolone. J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):345-50. Epub 2005 Sep 20.
21.
22.
23.
24.
Schwarz S, Meinck HM, Storch-Hagenlocher B. Intravenous immunoglobulins in multiple sclerosis. An update. Nervenarzt. 2009 Aug;80(8):918-28. Clegg A, Bryant J, Milne R. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review. Health Technol Assess. 2000;4(9):i-iv, 1-101. Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011 Sep;9(3):40916. Khatri I A, Mehboob N, Ahmad A, Siddiqui M, Siddiqui NS. Use of mitoxantrone in multiple sclerosis experience at Shifa International Hospital, Islamabad, Pakistan. Pak J Neurol Sci 2012; 7(1):1_ 4.
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