Movement Disorders Associated With CLIPPERS Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory disease of unknown etiology. Movement disorders have been mentioned only briefly in a few reported cases.1
Case 1 A woman aged 65 years2 developed subacute right upper limb tremor and dystonia associated with progressive gait ataxia, dysarthria, vertigo, lethargy and confusion. Examination revealed right upper limb rest tremor predominantly affecting the forearm, moderate intention tremor, and intermittent postural tremor accompanied by dystonic posturing (see Video Segment 1). There was mild dystonia of the right leg during walking. Surface electromyography (EMG) recordings revealed 3-Hz to 4-Hz EMG bursting in the right upper limb muscles. A cerebral magnetic resonance image (MRI) demonstrated contrast-enhancing lesions in the bilateral brachium pontis, pons, and cerebellum, typical of CLIPPERS, in addition to high signal in the right dentate nucleus (Fig. 1A,B). Cerebellar biopsy demonstrated a perivascular, lymphohistiocytic, inflammatory infiltrate and reactive gliosis. Treatment with high-dose corticosteroids lead to dramatic clinical and radiological improvement, although the tremor persisted. Treatment with a combination of levodopa and botulinum toxin injections resulted in marked symptomatic and functional improvement of tremor.
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10-mec to 25-msec EMG bursts in the left upper limb that were synchronous in the forearm antagonist muscles (Fig. 1C), with demonstration of a preceding cortical spike on back-averaging, consistent with epilepsia partialis continua (EPC). Cerebral MRI revealed punctate and linear enhancement in the brainstem, cerebellum, and pons with extension into the left thalamus (Fig. 1D) as well as hemispheric white matter involvement, although no specific lesion was identified in the cortical hand or face regions. Extensive serological investigations were negative.3 There was no improvement in the jerks despite treatment with azathioprine and prednisone for two years, and she declined further immunomodulatory therapy. Examination nine years after onset revealed ataxia and spasticity as well as ongoing jerks. Progress cerebral MRI scans revealed progressive atrophy of the brainstem and cortex without enhancement. In our first case, the phenomenology was suggestive of a Holmes tremor, consisting of a high-amplitude, 4-Hz tremor that was evident during rest, posture, and action.4 The onset of tremor corresponded with the appearance of an inflammatory focus in the right cerebellar hemisphere. In the second case, the diagnosis of EPC was supported by neurophysiological studies, which demonstrated the presence of a preceding cortical spike on back-averaging that was time-locked to EMG bursts of < 100-msec duration.5 Although cortical lesions were not identified, the presence of cortical atrophy on progress scans was suggestive of grey matter involvement. Movement disorders may be part of the presentation of CLIPPERS, presumably because of strategic lesions occurring as part of the underlying disease process, and can persist despite chronic immunosuppressive therapy, requiring targeted symptomatic treatment.
Legends to the Videos Case 2 3
The second woman developed jerks that affected her left hand and face at age 56 years, two years after the development of CLIPPERS, which manifested as ataxia, vertigo, ophthalmoplegia, and mild left-sided facial weakness (see Video Segment 2). The movements were near continuous, persisting during sleep. Irregular palatal movements also were observed. There was no associated action or reflexsensitive myoclonus. Neurophysiological recordings revealed
-----------------------------------------------------------Additional Supporting Information may be found in the online version of this article. *Correspondence to: Dr. Victor Fung, Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW 2145, Australia; [email protected]
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 27 June 2013; Revised: 30 August 2013; Accepted: 10 September 2013 Published online 12 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25719
Movement Disorders, Vol. 29, No. 1, 2014
Video Segment 1. Patient 1 demonstrates a slow, irregular, right upper limb tremor predominantly affecting the forearm with a supination/pronation component at rest and a mildmoderate postural and intention tremor. Dystonic posturing is seen in the right upper limb, with elevation of the shoulder and flexion of the metacarpophalangeal joints in the nose-targeting position. There is difficulty with rapid motor tasks in the right upper limb. Video Segment 2. Patient 2 demonstrates jerks in her left hand and left lower face with irregular palatal movements. Ainhi D. Ha, MBBS, FRACP,1 John D. Parratt, MBChB, MD, FRACP,2 Sangamithra Babu, MBBS,1 Samuel D. Kim, MBBS, BsC(Med), MD, FRACP,1 Neil Mahant, MBBS, PhD, FRACP,1 John O’Neill, MD, FRACP,3 Jean-Pierre Halpern, MBBS(Hons), PhD, FRACP,4 Victor S. C. Fung, PhD, FRACP1,5* 1 Movement Disorders Unit, Westmead Hospital, Westmead, Sydney, New South Wales, Australia; 2Department of Neurology, Royal North Shore Hospital, St. Leonards,
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FIG. 1. (A) In patient 1, a T1-weighted magnetic resonance image (MRI) of the brain with gadolinium demonstrates contrast-enhancing lesions in the brachium pontis, pons, and cerebellum. (B) Also in patient 1, an axial fluid-attenuated inversion recovery MRI brain at the level of the brainstem demonstrates lesions in the right dentate nucleus and the left brachium pontis. (C) In patient 2, surface electromyography (EMG) recordings were obtained from the left upper limb and the left risorius at rest. EMG bursts were synchronous in forearm muscles but were not synchronous between forearm muscles and risorius. (D) Also in patient 2, a T1-weighted MRI of the brain with gadolinium demonstrates punctate and linear areas of enhancement in the brainstem.
Movement Disorders, Vol. 29, No. 1, 2014
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Sydney, New South Wales, Australia; 3Department of Neurology, St. Vincents Hospital, Darlinghurst, Sydney, New South Wales, Australia; 4Department of Neurology, Sydney Adventist Hospital, Wahroonga, Sydney, New South Wales, Australia; 5Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia Acknowledgements: We thank the patients and their families for
TABLE 1. Association between clinical subtypes of PD and mortalitya Subtype
1 2 3 4
No. of Deaths/No. of Patients (%)
6/169 3/45 22/103 6/26
(3.6) (6.7) (21.4) (23.1)
HR (95% CI)
1.00 (Reference) 2.74 (0.65–11.60) 4.46 (1.77–11.22) 8.33 (2.57–27.03)
collaborating in this study.
Pittock SJ, Debruyne J, Krecke KN, et al. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain 2010;133:2626-2634.
Simon NG, Parratt JD, Barnett MH, et al. Expanding the clinical, radiological and neuropathological phenotype of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). J Neurol Neurosurg Psychiatry 2012;83:15-22.
Smith A, Matthews Y, Kossard S, Turner J, Buckland M, Parratt J. Neurotropic T-cell lymphocytosis: a cutaneous expression of CLIPPERS. J Cutan Pathol. In press.
Zeuner KE, Deuschl G. An update on tremors. Curr Opin Neurol 2012;25:475-482.
Cockerell OC, Rothwell J, Thompson PD, Marsden CD, Shorvon SD. Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK. Brain 1996;119 (pt 2):393-407.
Relation of Clinical Subtypes in Parkinson’s Disease With Survival It is increasingly recognized that Parkinson’s disease (PD) is a clinically heterogeneous disease, with wide variation in presence and severity of motor and non-motor symptoms and disease course. Overall, PD is associated with an increased mortality rate compared with the general population,1 but survival after disease onset differs considerably across patients. One might hypothesize that certain subgroups of PD patients have a worse prognosis in terms of mortality risk than others. It has been suggested that there are several clinical subtypes of PD.2-5 A data-driven cluster analysis, which was performed on baseline data from the “Profiling Parkinson’s Disease” (PROPARK) study and validated in an independent Spanish cohort, previously revealed four distinct clinical sub-
-----------------------------------------------------------*Correspondence to: Dr. Lonneke M. L. de Lau, Department of Neurology, Slotervaart Hospital, PO Box 90440, 1006 BK Amsterdam, the Netherlands; [email protected]
Funding agencies: This work was supported by a grant from the Dutch Parkinson’s Disease Society (J.J.v.H.). The funding source had no role in the study design, collection, analysis and interpretation of data, or writing of the report. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 3 February 2013; Revised: 11 July 2013; Accepted: 23 July 2013 Published online 3 September 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25652
Movement Disorders, Vol. 29, No. 1, 2014
a Values are expressed as the mortality HR with 95% CI for each subtype, with the most frequent subtype (subtype 1) as the reference category. Abbreviations: CI, confidence interval; HR, hazard ratio.
types of PD (denoted as subtypes 1, 2, 3, and 4).6 Patients who have subtype 1 PD are characterized by an overall mild severity in all clinical domains, subtype 2 is predominantly characterized by severe and frequent motor complications, patients with subtype 3 are affected mainly on nondopaminergic domains (postural instability/gait disturbance, cognitive impairment, autonomic dysfunction, depression, and psychosis) without prominent motor complications, and those with subtype 4 are severely affected on all domains. 6 We compared survival in these clinical subtypes using follow-up data from the PROPARK study. The PROPARK study is a longitudinal cohort study of 414 patients with PD who undergo extensive annual evaluation of a large number of motor and non-motor symptoms. The recruitment procedure has been described in detail elsewhere.7 The medical ethical committee of the Leiden University Medical Center approved the study, and written informed consent was obtained from all patients. At baseline (May 2003 to September 2005) and at five annual follow-up visits, all patients received a standardized assessment of different clinical domains (all assessments were described previously in detail).7 Classification according to the four clinical subtypes was available for 343 patients (83%) in the cohort. The remaining patients were excluded from the cluster analyses because of stereotactic surgery (n 5 18) or missing data (n 5 53). When patients did not respond to their yearly invitation for the follow-up assessments, the patient’s general practitioner was contacted to verify the vital status. In case the patient had died, the general practitioner provided the exact mortality date. Unadjusted survival in four clinical subtypes was examined using Kaplan-Meier analysis and was compared using the log-rank test. The association of individual subtypes with mortality was evaluated by means of Cox proportional hazards regression analyses that were adjusted for age, sex, and disease duration, using the most common subtype (subtype 1) as the reference category. During the follow-up period, 37 patients (10.8%) died. Unadjusted survival differed significantly across the four clinical subtypes (log-rank test; P 5 0.000). Subtype 3 and 4 were associated with a significantly increased risk of mortality compared with subtype 1 (Table 1). Our finding that mortality rates differed significantly across clinical subtypes lends support to the concept of distinct subgroups of PD patients displaying differences in clinical profile, disease course, and prognosis. Survival was most strongly reduced in subtypes 3 and 4, both of which were characterized