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• The complex NMDAR-antibody associated movement disorder is highly-distinctive
  James A Varley, Anthony E Lang, Kailash P Bhatia and Sarosh R Irani
  Published on: 16 May 2019
• Reply to: The Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study
  Philip D Thompson, Thomas Kimber and Timothy Kleinig
  Published on: 16 May 2019

• Published on: 16 May 2019

  The complex NMDAR-antibody associated movement disorder is highly-distinctive

  • James A Varley, Clinical DPhil student University of Oxford
  • Other Contributors:
    • Anthony E Lang, Professor
    • Kailash P Bhatia, Professor
    • Sarosh R Irani, Associate Professor

  We thoroughly enjoyed reading the comment on our paper which analysed expert ratings of the movement disorder associated with NMDAR antibody-encephalitis.1 Thompson et al’s elegant pathophysiological explanation provides an excellent framework of the most plausible neural structures involved in NMDAR-antibody encephalitis. Further, they note these movements can occur in semi-conscious patients, and this concurs well with the previous description of anti-gravity movements in the context of ‘status dissociatus’.2 A review of our 76 videos, revealed Thompson et al’s account of “variable, complex jerky semi-rhythmic movements….in the obtunded state” in 45 (59%) of cases. Therefore, this complex description was not present in almost half of patients. Furthermore, our recent clinical experiences note some NMDAR-antibody patients with abnormal movements but without obtundation: perhaps, given the known stepwise progression of many cases, this is a function of increasingly early disease recognition.3

  By contrast to Thompson et al, our published study design intentionally used conventional phenomenological terms to define the movement disorder associated with NMDAR antibody-encephalitis.1 This approach aimed to define a pragmatic method, available to all clinicians, which could identify and faithfully communicate this complex movement disorder, with the important aim of earlier disease recognition. The results identified a dominant set of recognised classifications – dyston...

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  We thoroughly enjoyed reading the comment on our paper which analysed expert ratings of the movement disorder associated with NMDAR antibody-encephalitis.1 Thompson et al’s elegant pathophysiological explanation provides an excellent framework of the most plausible neural structures involved in NMDAR-antibody encephalitis. Further, they note these movements can occur in semi-conscious patients, and this concurs well with the previous description of anti-gravity movements in the context of ‘status dissociatus’.2 A review of our 76 videos, revealed Thompson et al’s account of “variable, complex jerky semi-rhythmic movements….in the obtunded state” in 45 (59%) of cases. Therefore, this complex description was not present in almost half of patients. Furthermore, our recent clinical experiences note some NMDAR-antibody patients with abnormal movements but without obtundation: perhaps, given the known stepwise progression of many cases, this is a function of increasingly early disease recognition.3

  By contrast to Thompson et al, our published study design intentionally used conventional phenomenological terms to define the movement disorder associated with NMDAR antibody-encephalitis.1 This approach aimed to define a pragmatic method, available to all clinicians, which could identify and faithfully communicate this complex movement disorder, with the important aim of earlier disease recognition. The results identified a dominant set of recognised classifications – dystonia, stererotypies and chorea – with a paucity of tremor. In agreement with Thompson et al’s observations, it revealed some additional under-represented features. These were within our ‘other’ classification category (Figure 1D), and included mutism, stupor, myorhythmia, myokymia, tics, opisthotonus, ataxia, dyskinesias, waxy flexibility, oculogyric crises, athetosis, agitation, startle and vocal perseveration. However, we noted in our discussion that even the expert raters found it difficult to accurately describe this movement disorder within the predictable constraints of preconceived and established categorisations, and much of their feedback reflected a dissatisfaction with the final category chosen. Quantitatively, and by comparison to the other mixed movement disorders they rated, this limitation was strikingly reflected by the appreciably poorer inter-rater variability and the significantly more descriptive terms used to capture the essence of this movement disorder (P<0.0001).

  Indeed, our findings are best interpreted within the intrinsic framework of movement disorder nomenclature. By extension, and particularly to the expert eye, we agree with Thompson et al that the disorder is often even more distinctive than this rare combination would suggest. In fact, in some cases, it may be unique. Interestingly, use of the term ‘unique’ may only be inaccurate given some of the closest mimics include ketamine / phencyclidine use and GRIN1A mutations. Of course, all of these imply the targeted specific-NMDAR modulation is at the core of this network-based pathophysiology.

  Overall, within inevitable contemporary nomenclature constraints, we anticipate that the constellation of dystonia, stereotypies and chorea, with limited tremor, will provide a comprehensive, clear and concise message to clinicians and alert them to the possibility of this highly-treatable disorder. Yet, in future, perhaps this multifaceted movement disorder merits its own nomenclature to better emphasise the distinctive nature of the clinical observations. However, a term such as NMDAR-antibody associated movement disorder would be self-fulfilling and perhaps divert from the aim of its accurate recognition. Therefore, a reliance on conventional terms will yet be necessary to communicate this entity.

  References
  1. Varley JA, Webb AJS, Balint B, et al. The Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study. J Neuro Neurosurg Psychiatry 2018;
  2. Stamelou M, Plazzi G, Lugaresi E, et al. The distinct movement disorder in anti‐NMDA receptor encephalitis may be related to status dissociatus: A hypothesis. Mov Disord. 2012;27(11):1360–1363.
  3. Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010;133(Pt 6):1655–1667.

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  Conflict of Interest:
  None declared.

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• Published on: 16 May 2019

  Reply to: The Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study

  • Philip D Thompson, Emeritus Professor of Neurology University of Adelaide
  • Other Contributors:
    • Thomas Kimber, Consultant Neurologist
    • Timothy Kleinig, Clinical Stroke director

  We read with interest the description of the movement disorder manifestations in patients with N-methyl-D-aspartate receptor antibody mediated encephalitis (NMDAR-AbE) by a panel of movement disorders experts (1). The authors conclude that the co-existence of dystonia, chorea and stereotypies within the same patient, variability in phenomenology within the course of a single day and evolution over time, are helpful pointers to the diagnosis of NMDAR-AbE and therefore early treatment. We agree with this conclusion. However, this analysis overlooks consideration of the distinctive, if not unique, phenomenology of the “classical” movement disorder of NMDAR-AbE (2).

  In our earlier description of this complex movement disorder we reported the presence of variable, complex, jerky semi-rhythmic bulbar and limb movements, associated with posturing and oculogyric crises, but in summarising the overall clinical syndrome we deliberately avoided conventional movement disorder terms because none captured the entire clinical picture (2). Classification of a movement disorder, particularly when complex, is guided by the most obvious, dominant or overwhelming clinical feature. The ‘classical’ movement disorder in NMDAR-AbE is complex but as acknowledged by the expert reviewers, is not typical of any of the movement disorder categories (1). Stereotypies are purposeless repetitive motor behaviours that occur when awake and are interrupted by a shift in attention or distraction. Dy...

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  We read with interest the description of the movement disorder manifestations in patients with N-methyl-D-aspartate receptor antibody mediated encephalitis (NMDAR-AbE) by a panel of movement disorders experts (1). The authors conclude that the co-existence of dystonia, chorea and stereotypies within the same patient, variability in phenomenology within the course of a single day and evolution over time, are helpful pointers to the diagnosis of NMDAR-AbE and therefore early treatment. We agree with this conclusion. However, this analysis overlooks consideration of the distinctive, if not unique, phenomenology of the “classical” movement disorder of NMDAR-AbE (2).

  In our earlier description of this complex movement disorder we reported the presence of variable, complex, jerky semi-rhythmic bulbar and limb movements, associated with posturing and oculogyric crises, but in summarising the overall clinical syndrome we deliberately avoided conventional movement disorder terms because none captured the entire clinical picture (2). Classification of a movement disorder, particularly when complex, is guided by the most obvious, dominant or overwhelming clinical feature. The ‘classical’ movement disorder in NMDAR-AbE is complex but as acknowledged by the expert reviewers, is not typical of any of the movement disorder categories (1). Stereotypies are purposeless repetitive motor behaviours that occur when awake and are interrupted by a shift in attention or distraction. Dystonia and chorea characteristically accompany voluntary or postural movements, subsiding with rest and disappearing during sleep. We drew attention to the occurrence of the movement disorder in the obtunded state, ‘awake unresponsiveness’ or coma, the disappearance of the movements following recovery of consciousness, and highlighted the modulation of movements with sensory stimuli. These features are not typical of stereotypies, dystonia or chorea. Mutism, waxy flexibility, catatonia, oculogyric crises, opisthotonus and other signs occur as elements of the clinical picture but are not dominant features of the syndrome.

  We suggested the occurrence of these movements in obtunded states provided an important clue to the pathophysiology (2) and drew attention to similar movements in phencyclidine and ketamine intoxication associated with “dissociative anaesthesia” (ie, loss of responsiveness to external stimuli, also referred to as akinetic mutism, coma vigil or wakeful unresponsiveness in the neurological literature), stupor or coma. The initial neuropsychiatric and behavioural abnormalities suggest frontal-limbic involvement but this does not account for the altered conscious state and movement disorder. In order to explain this we postulated progression to diffuse cortical NMDA receptor blockade, interrupting glutamate transmission and suspending or “silencing” supratentorial descending tonic GABAergic inhibitory input to brainstem reticular systems, releasing patterned rhythmic movements such as chewing, bruxism, facial grimacing, frowning, lip smacking, tongue movements and rudimentary limb movements from pattern generators within pontomesencephalic locomotor regions or the pontomedullary reticular formation. These movements are analogous to primitive motor synergies such as undulatory gill and fin motion in fish, chewing and stepping. Decerebrate posturing, opisthotonus and oculogyric crises may be generated by similar mechanisms releasing the brainstem reticular systems from supratentorial control. As conscious state, awareness and responsiveness improve the movements subside, indicating return of the normal hierarchical descending hemispheric control over the brainstem centres. This model therefore explains the observed correlation between level of consciousness and movement severity.

  References
  1. Varley JA, Webb AJS, Balint B, et al. The movement disorder associated with NMDAR antibody encephalitis is complex and characteristic: an expert video rating study. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2018-318584.
  2. Kleinig TJ, Thompson PD, Matar W, et al. The distinctive movement disorder of ovarian teratoma associated encephalitis. Mov Disord 2008, 23: 1256-1261.

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  Conflict of Interest:
  None declared.

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