Multiple Sclerosis

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Rapidly progressive course of very late onset multiple sclerosis presenting with Parkinsonism: case report T Schultheiss, H Reichmann and T Ziemssen Mult Scler published online 4 October 2010 DOI: 10.1177/1352458510384306 The online version of this article can be found at: http://msj.sagepub.com/content/early/2010/10/02/1352458510384306

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Case Study

Rapidly progressive course of very late onset multiple sclerosis presenting with Parkinsonism: case report

Multiple Sclerosis 0(00) 1–5 ! The Author(s) 2010 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458510384306 msj.sagepub.com

T Schultheiss, H Reichmann and T Ziemssen

Abstract Multiple sclerosis mainly affects young adolescents, making late-onset multiple sclerosis a rarity and diagnostic challenge, particularly for cases after age 80 years. We present an 82-year-old patient with multiple sclerosis with very late onset. As well as spastic paraplegia, additional Parkinsonism secondary to demyelination in the basal ganglia was observed in this case. In most publications, spinal cord lesions were more common in late-onset multiple sclerosis which, in contrast, could not be found in our case. Despite different treatment strategies, rapid clinical deterioration and death after about 2 years of disease course occurred. Further discrimination in late-onset multiple sclerosis (50–70 years) and multiple sclerosis with very late onset (above 70 years) might be considered. Future trials to elucidate potential benefit of immunosuppressive (and neuroprotective) therapies in these age groups are mandatory. Keywords multiple sclerosis, progressive Date received: 30th March 2010; revised: 28th July 2010; accepted: 18th August 2010

Introduction Multiple sclerosis (MS) is most commonly considered to be a disease affecting only young adults between 20 and 40 years, with a preponderance of females. However, about 40% of MS patients experienced their first MS symptoms after age 40.1 Late-onset MS (LOMS) is generally considered as starting after age 50. According to different retrospective studies, the prevalence of LOMS ranges between 4% and 9.4%.1–3 Several studies in the last few years have tried to define the initial clinical profile, disease course and progression in LOMS. Motor and cerebellar impairment is most frequently observed at first presentation,2 with progressive involvement of other functional systems, particularly sensory and sphincter dysfunction.4 In contrast to other disease entities, for example cerebrovascular diseases, the association between MS and Parkinsonism is rarely reported6 and it is still open to debate as to whether it is causal or coincidental.7 In a number of studies the primary progressive disease course is more commonly observed in the elderly, ranging from 32% to 83%,2,3,7,8 with an unusually high

prevalence in males.2 LOMS is typically associated with poor prognosis,2,3 which may have implications for early initiation of aggressive therapy.9 Both mean duration of the relapsing–remitting period and the mean time from onset of the disease to the beginning of the secondary phase is significantly shorter in LOMS than in young-onset MS (YOMS).5 However, one recent publication has shown that once the disease course is set, progression is similar, even if the onset of MS occurs late or during adulthood.9 There have been few reports to date of patients experiencing their first symptoms at the age of 60 years or older.7,10 Here we describe the clinical disease course of a patient with MS with very late onset presenting with L-dopa-unresponsive Parkinsonism

Department of Neurology, University Hospital Gustav Carus, Technische Universita¨t Dresden, Germany. Corresponding author: Thorsten Schultheiss, Department of Neurology, University Hospital Gustav Carus, Technische Universita¨t Dresden, Germany Email: [email protected]

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starting at the age of 80 years, with rapid clinical deterioration.

Case report We report on an 82-year-old Caucasian male presenting with a progressive gait disorder associated with repetitive falls. Pre-existing conditions included type-2 diabetes mellitus and brady-tachycardia syndrome with atrial fibrillation. The first contact was in February 2008 with symptoms lasting for about half a year. Clinical examination revealed dysarthria, moderate gait ataxia with spasticity and tendency for non-directional falls, and discrete Parkinsonism (hypomimia, bradykinesia and right-sided rigor with cogwheel phenomenon). Walking distance was 200 m at that time. The cerebral magnetic resonance imaging (MRI) showed multifocal supratentorial and infratentorial white matter lesions with slight gadolinium enhancement (Figure 1a–c) and MS plaques in both basal

ganglia (left > right; Figure 2). Spinal MRI revealed no demyelination and was normal apart from moderate degenerative changes. Cerebrospinal fluid (CSF) analysis demonstrated normal white cell count, but unmatched oligoclonal bands were detected. Pathological latencies of visual, somatosensory, and motor evoked potentials were shown by electrophysiological studies. Despite the patient’s advanced age, primary progressive MS was suspected and a standardized test battery for differential diagnosis was performed, excluding sarcoidosis, vasculitis, Lyme disease, and vitamin B12 deficiency. Isolated vasculitis of the nervous system was taken into specific consideration and was initially supported by an elevated protein level of 853 mg/l in the CSF, but systemic markers as well as erythrocyte sedimentation rate were all normal. MRI angiography showed no abnormalities of the cerebral vessels. With regard to Parkinsonism, additional nuclear imaging was performed, and idiopathic Parkinson’s disease

Figure 1. Cerebral magnetic resonance imaging (T1-weighted image) showing hypointense lesions with gadolinium enhancement in the periventricular white matter and in the left cerebellar peduncle.

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Schultheiss et al.

3 In September 2008, there was a further deterioration in gait ataxia and walking distance was reduced to 10 m only with the aid of a walking frame. Home nursing became necessary. The patient still refused to receive an escalating immunotherapy. The following contacts were essentially made by phone because a regular follow-up in our outpatient department could not be maintained. In December 2008, the patient became wheelchair bound, and 3 months later bed-ridden. After about 2 years of disease course, in July 2009, the patient died due to aspiration pneumonia.

Discussion

Figure 2. Cerebral magnetic resonance imaging showing hyperintense periventricular white matter lesions in the T2-weighted image.

was excluded by [18F]-fluoro-L-dopa (F-DOPA) kinetics with positron emission tomography (PET) (Figure 3). Owing to MS plaques in the basal ganglia, secondary Parkinsonism was suspected and dopaminergic treatment initiated, resulting in slight improvement of gait. Owing to limited causal therapeutic alternatives in primary progressive MS, an individual treatment attempt with high-dose glucocorticoid treatment was initiated using i.v. prednisolone (1000 mg/day) for 5 consecutive days, and the patient was sent to rehabilitation. Some 5 months later, in July 2008, the walking distance was further reduced to about 50 m. Dysarthria was progressive and discrete dysphagia became evident. Expanded Disability Status Scale was 6.5. Cerebral MRI showed a new periventricular T2-lesion, confirming the diagnosis of primary progressive MS by dissemination in time. In addition, there was a remarkable amount of black holes in the periventricular white matter, and global brain atrophy. Previous glucocorticoid treatment had no effect, whereas physiotherapy during rehabilitation enabled stabilization of disease progression for a short period. More aggressive immunosuppressive therapy with mitoxantrone was considered, but refused by the patient primarily due to its potential cardiomyopathic side effects. The patient was discharged and continuous physiotherapy recommended.

Very late onset of MS is infrequent and presents a diagnostic challenge. It is widely accepted that the diagnosis must be made after exclusion of other diseases or syndromes with a similar clinical scenario. These include cerebral or spinal ischaemia, vitamin B12 deficiency, primary lateral sclerosis, late-onset cerebellar ataxia, primary or secondary vasculitis, sarcoidosis, degenerative spinal disorders, cerebellar paraneoplastic disorders, and tropical spastic paraparesis. A standardized test battery for differential diagnosis should include brain and spinal MRI, lumbar puncture and additional laboratory tests. Here we describe the clinical disease course of a patient with MS of very late onset starting at the age of 80 years. The diagnosis was confirmed using the revised McDonald criteria for primary progressive MS.11 Although vasculitis was initially considered in differential diagnosis, erythrocyte sedimentation rate, MRI angiography and systemic markers were all normal. A brain biopsy was not performed as MS was more likely. A dual pathology of MS and additional ischaemic lesions (caused by vasculitis) contributing to a rapid disease course cannot be ruled out in certainty. Although a recent MRI study revealed typical multifocal supratentorial and infratentorial lesions without significant differences in YOMS and LOMS, spinal cord lesions were more common in LOMS.8 In contrast, our patient did not have any demyelination in the spinal cord. Movement disorders are rarely associated with MS, albeit there is occasional involvement of the basal ganglia with MS plaques. Paroxysmal dystonias, ballism/ chorea, and palatal myoclonus are most frequently observed, while Parkinsonism appears to be a very rare finding.5 It is still not known whether the association is causal or coincidental, and several case reports in the past have demonstrated both possibilities.6 In our patient, exclusion of idiopathic Parkinson’s disease was done by PET studies. MS plaques in the basal ganglia made us consider secondary Parkinsonism.

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Figure 3. Positron emission tomography with18F-DOPA showing symmetrical enhancement in both caudate nuclei and putamen.

After initiation of dopaminergic therapy the patient experienced a slight benefit regarding gait. Treatment options in primary progressive MS are still restricted. Despite different treatment strategies (medical and non-medical), rapid deterioration of clinical condition and death 2 years after diagnosis could not be avoided in this case. As described previously, response to corticosteroids in LOMS patients is poorer than in YOMS.8 It could be argued that a more aggressive immunosuppressive therapy may have yielded better disease control. The use of mitoxantrone was considered but refused by the patient due to its potential cardiomyopathic side effects. This individual treatment proposal was essentially based on the gadolinium enhancement in the MRI, as there are no current available data so far. Results of the recently published Ollypus trial failed

to reduce the risk of disability progression in primary progressive MS patients treated with rituximab compared with placebo. Several reasons for poor response to immunosuppressive therapy in primary progressive MS have been discussed in recent publications, including changes in gene expression, altered T cell activity of the aging brain and immune system,2 and impaired oligodendrocyte progenitor recruitment and differentiation contributing to inadequate remyelination. The higher proportion of patients with a progressive disease course in the LOMS group has previously been attributed to a latent period, with the inflammatory relapsing– remitting phase either remaining clinically silent or not occurring.7,9 As previously reported, in older patients, misdiagnosis of MS and delay of diagnosis up to several years

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seems to be common.8 Further discrimination of LOMS (50–70 years) and MS with very late onset (above 70 years) for better evaluation of disease course and possible treatment options might be considered. Future trials to further elucidate a potential benefit of immunosuppressive (and neuroprotective) therapies in these age groups are mandatory. As long as the association of Parkinsonian features and MS remains unclear, a dopaminergic treatment attempt should always be taken into consideration. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement The authors declare that they have no conflicts of interest.

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4. Martinelli V, Rodegher M, Moiola L and Comi G. Lateonset multiple sclerosis: clinical characteristics, prognostic factors and differential diagnosis. Neurol Sci 2004; 25: S350–S355. 5. Tranchant C, Bhatia KP and Marsden CD. Movement disorders in multiple sclerosis. Mov Disord 1995; 10: 418–423. 6. Nociti V, Bentivoglio AR, Frisullo G, Fasano A, Soleti F, Iorio R, et al. Movement disorders in multiple sclerosis: causal or coincidental association? Mult Scler 2008; 14: 1284–1287. 7. Hooge JP and Redekop WK. Multiple Sclerosis with very late onset. Neurology 1992; 42: 1907–1910. 8. Kis B, Rumberg B and Berlit P. Clinical characteristics of patients with late-onset multiple sclerosis. J Neurol 2008; 255: 697–702. 9. Tremlett H and Devonshire V. Is late-onset multiple sclerosis associated with a worse outcome? Neurology 2006; 67: 954–959. 10. Abe M, Tsuchiya K, Kurosa Y, Nakai O and Shinomiya K. Multiple Sclerosis with very late onset: a report of a case with onset at age 82 years and review of the literature. J Spinal Disord 2002; 13: 548–549. 11. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2007; 50: 121–127.

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