Accepted Manuscript Treatment of Post Anoxic Action Myoclonus with Intrathecal Baclofen: A Case Report James A. Whitlock, Jr., MD, Ryan W. Dumigan, DPT PII: S1934-1482(17)30152-1 DOI: 10.1016/j.pmrj.2017.12.010 Reference: PMRJ 2041 To appear in: PM&R Received Date: 14 February 2017 Revised Date: 16 December 2017 Accepted Date: 22 December 2017 Please cite this article as: Whitlock Jr. JA, Dumigan RW, Treatment of Post Anoxic Action Myoclonus with Intrathecal Baclofen: A Case Report, PM&R (2018), doi: 10.1016/j.pmrj.2017.12.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT RI PT Intrathecal baclofen for action myoclonus Treatment of Post Anoxic Action Myoclonus with Intrathecal SC Baclofen: A Case Report M AN U James A. Whitlock, Jr. MD1 and Ryan W. Dumigan DPT2 1 VA Medical Center, Manchester, NH, USA 2 Healthsouth Rehabilitation Hospital, Concord, NH, USA Corresponding Author: TE D (Research conducted at Northeast Rehabilitation Hospital Network, Salem, NH, USA) James A. Whitlock, Jr., MD Department of Rehabilitation 718 Smyth Road EP VA Medical Center AC C Manchester, NH 03104 Phone: 603-624-4366 ext 6054 Email: james.whitlock@va.gov Fax: 866- 865-0061 Word count: 997 No funding was received for this study. 1 ACCEPTED MANUSCRIPT RI PT Intrathecal baclofen for action myoclonus Treatment of Post Anoxic Action Myoclonus with Intrathecal M AN U SC Baclofen: A Case Report AC C EP TE D No funding was received for this study. ACCEPTED MANUSCRIPT 1 Abstract A case of severe action myoclonus following pulmonary arrest is described. 3 Although there was benefit from oral pharmacotherapy, action myoclonus remained 4 disabling. A favorable response to baclofen during an intrathecal trial led to eventual 5 placement of an intrathecal baclofen pump. The present case illustrates the potential 6 utility of intrathecal baclofen for treating this condition. Keywords 9 myoclonus, action; anoxia; baclofen 10 11 Introduction 12 M AN U 8 SC 7 RI PT 2 Action myoclonus is an arrhythmic muscle jerking, often disabling in frequency and amplitude, affecting trunk and/or limbs during intentional movement. When this 14 condition develops days to weeks after hypoxic encephalopathy, it becomes the defining 15 feature of the Lance Adams Syndrome (LAS)(1). The degree of functional incapacity 16 caused by this disorder is generally profound and, in most cases, it is the main source of 17 disability. Intellect in these cases is generally preserved (1,2,3). While the condition 18 may improve slowly with time, the duration of disabling impact is indefinite. Anti- 19 myoclonic medications such as levetiracetam, valproate, clonazepam and zonisamide can 20 have a favorable impact and have often been used as monotherapy or in combination. EP AC C 21 TE D 13 The present case documents our attempt to achieve functional improvement using 22 intrathecal baclofen in a patient with LAS who remained severely disabled one year after 23 onset. 1 ACCEPTED MANUSCRIPT 24 25 26 Case Presentation A 48-year-old male with a three-month history of enterococcal aortic valve endocarditis was admitted to the hospital with increasing shortness of breath. 28 Transesophageal probe for attempted cardioversion of atrial flutter was performed the 29 day after admission and was complicated by cardiovascular collapse with respiratory 30 arrest. Marked encephalopathy followed and myoclonus was first noticed about a week 31 after resuscitation. Attempts at control were attempted with levetiracetam and 32 clonazepam, both of which were discontinued during periods of marked metabolic 33 instability. Acute renal failure required hemodialysis for about two months. There was 34 also a marked early elevation of liver enzymes. His acute hospital course was prolonged 35 and further complicated by a second near cardiopulmonary arrest thought to be due to 36 sepsis. He continued to have periods of unresponsiveness with apnea. MRI of the brain 37 performed shortly after the second cardiovascular crisis showed evidence of acute left 38 parietal and cerebellar infarction. EEGs four days and again one week post-event showed 39 changes consistent with severe generalized cortical dysfunction. SC M AN U TE D EP 41 He entered an acute inpatient rehabilitation unit two months after onset of the first AC C 40 RI PT 27 42 pulmonary arrest. Upon admission, he was alert and somewhat conversant. Functionally 43 he was completely dependent in all areas of mobility and self care. He demonstrated 44 frequent, large amplitude multifocal myoclonic jerks involving extremities and trunk that 45 shook his bed or his chair, evoked and amplified by any attempts at voluntary movement. 46 2 ACCEPTED MANUSCRIPT 47 Initial attempts to mitigate action myoclonus involved levetiracetam which was titrated over the course of about two months to 2000 milligrams (mg) twice daily. 49 Clonazepam was concurrently prescribed and gradually increased to 1.5 mg TID. Higher 50 doses were associated with problematic cognitive blunting. When disabling myoclonus 51 continued to be evoked by any activity that involved proximal and truncal musculature, 52 divalproex sodium was begun but was discontinued within two weeks because of 53 increasing confusion. SC RI PT 48 54 There was a substantial improvement in myoclonus with the oral agents, but the 56 degree of disability related to proximal lower extremity and upper extremity myoclonus 57 continued to be very high. There remained near total dependence for activities of daily 58 living, mobility and transfers six months after the onset of the condition. M AN U 55 60 TE D 59 Six months post initial anoxic event an intrathecal baclofen trial was undertaken with the understanding that this was an “off-label” non-FDA approved use of this 62 medication. A lumbar bolus injection of 75 micrograms (mcg) of baclofen was 63 performed. The effects of the bolus were measured with a 73 item Unified Myoclonus 64 Rating Scale (UMRS)(4) designed to capture both subjective and objective impact of 65 myoclonic movement disorders using measurable features (frequency and amplitude of 66 movements) and functional activities (eg.- writing, drinking from a cup, transfers, 67 walking). The two sections of the UMRS thought by its developers to be best at 68 measuring treatment effect improved by 33% (“action myoclonus” measures) and 22% 69 (“functional tests” portion) during the trial. Performance of skilled upper extremity AC C EP 61 3 ACCEPTED MANUSCRIPT 70 movement as demonstrated by spiral drawing and of proximal lower extremity control 71 were particularly evident. 72 During the weeks after the baclofen trial there was deterioration in heart and 74 kidney function due to severe aortic and tricuspid insufficiency and intractable heart 75 failure. Cognitive status was deteriorating and it was unclear whether metabolic disorder, 76 medication adverse effect and/or depression were factors. Levetiracetam and clonazepam 77 were gradually decreased to 1000 mg BID and 0.5 mg BID respectively without gross 78 functional change in action myoclonus. The patient was referred to a tertiary center for 79 valve replacement surgery. Eight months after the initial hypoxic event he underwent 80 aortic valve replacement and tricuspid annuloplasty with subsequent resolution of 81 congestive heart failure. The myoclonus transiently worsened during a temporary lapse 82 in clonazepam, improving immediately upon resumption. Zonisamide was added and 83 titrated up to 150 mg QID with some reduction in intensity of myoclonus. He continued 84 rehabilitation on an outpatient level after discharge to home just over 11 months after 85 initial presentation. SC M AN U TE D EP 87 Thirteen months after presentation, having finally attained a state of medical AC C 86 RI PT 73 88 stability and before commencement of intrathecal baclofen therapy, the UMRS Action 89 Myoclonus score had improved by 27% while the Functional Scale remained unchanged 90 (table 1 – pre-bolus compared to pre-pump scores) with a high level of dependency in all 91 ADLs. He required one person assist for transfers and was able to take a few steps with 92 max assist in a rolling walker. After obtaining written informed consent, a Medtronic™ 4 ACCEPTED MANUSCRIPT SynchroMed II pump was placed. The catheter terminated at the T6 spinal level. Simple 94 continuous dosing of intrathecal baclofen was set at 99.6 mcg per 24 hours. During the 95 months that followed, there was an attempt to find a baclofen dose that would have a 96 significant functional impact upon transfer and mobility. His function seemed to stabilize 97 at an intrathecal baclofen dose of 280 mcg per day, given on a simple, continuous 24- 98 hour schedule. A repeat UMRS rating at that point showed a score of 43 on the Action 99 Myoclonus subscale and 12 on the Functional scale – 26% and 22% improvements 100 respectively (highlighted numbers table 1). He became able to complete the drawing of a 101 spiral with each hand, pour water from one glass to another (spilling less than half) and 102 reach his mouth with a spoon containing water. Improvements post pump in “myoclonus 103 with action” came from marked reduction in frequency and amplitude of upper extremity 104 myoclonus. M AN U SC RI PT 93 106 107 Discussion TE D 105 The pathophysiology of post anoxic myoclonus is obscure. Animal data suggest that selective vulnerability to hypoxia of a subset of Purkinje cells in the cerebellar 109 vermis leads to disinhibition of gamma amino butyric acid (GABA)-ergic fastigial 110 nucleus which in turn leads to cell death in parts of the motor thalamus and reticular 111 formation. Those changes result in myoclonus in a rat model (5). There are several 112 reports documenting varying degrees of anti-myoclonic activity from oral agents which 113 have GABAergic or tryptophan increasing activity – (clonazepam, divalproex sodium, L 114 hydroxytryptophan) (2,6,7). Literature suggesting an anti-myoclonic effect of piracetam 115 led to the discovery that closely related levetiracetam can be very helpful in addressing AC C EP 108 5 ACCEPTED MANUSCRIPT 116 action myoclonus. The generally well-tolerated anticonvulsant zonisamide has also 117 found anecdotal application (7). 118 Baclofen is a GABAβ-ergic agent that was first reported as showing therapeutic benefit for post-anoxic action myoclonus in 1980 (8). There is only one other case 120 report of intrathecal baclofen being successfully used. This occurred much earlier in the 121 clinical course of a young man with LAS (9). In that case, major gains in functional 122 mobility followed pump implantation. Given the evidence against there being any 123 failure of descending inhibitory influences upon alpha motor neurons in LAS, it is 124 surprising that a GABAβ -agonist with localized spinal activity would be therapeutic 125 (1,10). SC M AN U 126 RI PT 119 Interestingly, our patient’s rating of disability was higher during the ‘pre’ and ‘post’ pump implant period and the baclofen trial period. Note that these events were at 128 least 6 months apart. It is our opinion that early in his illness, there was a tendency to 129 overestimate abilities for feeding, hygiene and dressing that may have been related to the 130 psychological defense of denial. Despite this, his global assessment of disability at those 131 sessions was equivalent at “I have marked disability. There are many things that I cannot 132 do even with help.” 134 135 EP AC C 133 TE D 127 Conclusion This is only the second reported case of showing functional improvement from 136 intrathecal baclofen in post-anoxic action myoclonus. This case is distinctive with 137 respect to marked upper extremity improvement over a year after onset of LAS. The 138 mechanism of therapeutic effect is unclear. This form of treatment should be further 6 ACCEPTED MANUSCRIPT 139 investigated for its potential to restore function in persons with prolonged post-anoxic 140 action myoclonus, including persons with more chronic forms of the condition. 142 RI PT 141 Acknowledgement 144 We are grateful to our patient and his family for the strength, patience, and generosity of 145 spirit that they have shown throughout their difficult journey. SC 143 146 Declaration of Conflicting Interests 148 The authors declared no potential conflicts of interest with respect to the research, 149 authorship, and/or publication of this article. 150 M AN U 147 Funding 152 The authors received no financial support for the research, authorship, and/or publication 153 of this article. 156 157 158 159 EP 155 AC C 154 TE D 151 160 161 7 ACCEPTED MANUSCRIPT 162 163 164 References 1. Lance JW, Adams RD. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain. 1963; 86:111-136. 166 167 RI PT 165 2. Frucht S, Fahn S. The clinical spectrum of posthypoxic myoclonus. Mov Disord. 2000;15 (Suppl 1):2-7. SC 168 3. Werhan KJ, Brown P, Thompson PD, Marsden CD. The clinical features and 170 prognosis of chronic posthypoxic myoclonus. Mov Disord. 1997; 12(2):218 M AN U 169 171 4. Frucht SJ, Leurgans SE, Hallet M, Fahn S. The Unified Myoclonus Rating Scale: 173 In: Adv Neurol. Vol. 89: Myoclonus and Paroxysmal Dyskinesias. 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The use of intrathecal baclofen therapy for myoclonus in a patient with Lance Adams syndrome. PM&R. 2011; 194 3:671-673. M AN U 193 195 10. Kroin JS, Ali A, York M, Penn R. The distribution of medication along the spinal 197 canal after chronic intrathecal administration. Neurosurg. 1993; 33(2):223-230. AC C EP TE D 196 9 ACCEPTED MANUSCRIPT Section scores of the Unified Myoclonus Rating Scale (UMRS)* over time. Range1 UMRS Section Pre-bolus Post-bolus Patient questionnaire 0 - 44 18 17 4 Myoclonus with action 0 - 160 79 53 5 Functional tests 0 - 20 18 5.6 * Pre-pump Post-pump 25 26 58 43 14 18 12 5.8 12.8 19.3 M AN U 1 Months post onset SC Table 1. RI PT Intrathecal baclofen for action myoclonus AC C EP TE D Sections pertaining to negative myoclonus, stimulus sensitivity and myoclonus at rest were omitted because those features were not observed in our patient. 1 Higher scores correspond to greater impairment and disability