Movement disorders and the osmotic demyelination syndrome

Parkinsonism and Related Disorders 19 (2013) 709e716

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Review

Movement disorders and the osmotic demyelination syndrome Aaron de Souza* Department of Neurology, Goa Medical College, Bambolim, Goa 403 202, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 February 2013 Received in revised form 11 April 2013 Accepted 13 April 2013

With the advent of MRI, osmotic demyelination syndromes (ODS) are increasingly recognised to affect varied sites in the brain in addition to the classical central pontine lesion. Striatal involvement is seen in a large proportion of cases and results in a wide variety of movement disorders. Movement disorders and cognitive problems resulting from ODS affecting the basal ganglia may occur early in the course of the illness, or may present as delayed manifestations after the patient survives the acute phase. Such delayed symptoms may evolve over time, and may even progress despite treatment. Improved survival of patients in the last few decades due to better intensive care has led to an increase in the incidence of such delayed manifestations of ODS. While the outcome of ODS is not as dismal as hitherto believed e with the acute akinetic-rigid syndrome associated with striatal myelinolysis often responding to dopaminergic therapy e the delayed symptoms often prove refractory to medical therapy. This article presents a review of the epidemiology, pathophysiology, clinical features, imaging, and therapy of movement disorders associated with involvement of the basal ganglia in ODS. A comprehensive review of 54 previously published cases of movement disorders due to ODS, and a video recording depicting the spectrum of delayed movement disorders seen after recovery from ODS are also presented. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Parkinsonism Osmotic demyelination Central pontine myelinolysis Extrapontine myelinolysis Movement disorders

Since Adams and Victor’s original description of “pontine myelinolysis” in alcoholic patients in 1959 [1], the disease subsequently named “osmotic demyelination syndrome” (ODS) in recognition of the importance of osmotic shifts in its pathogenesis has seen significant changes in diagnosis, course, and outcomes over the past few decades [2,3]. Increasingly common ante-mortem diagnosis after the advent of magnetic resonance imaging (MRI) has led to a revision of long-held concepts about the clinical course and prognosis of this disease. The recognition of osmotic demyelination in locations other than the central pons provided a pathophysiologic basis for the frequent association of movement disorders with ODS. These may be present in the acute phase or manifest as delayed sequelae, after recovery from the initial quadriparesis. With increasing survival from acute ODS due to better intensive care, it is likely that more delayed movement disorders will be seen as sequelae [4]. This review describes the epidemiology, clinical features and prognosis of movement disorders due to ODS in the modern era. 1. Epidemiology and pathophysiology Hitherto thought to be uncommon, ODS is increasingly reported today, and has accounted for 0.4e0.56% of admissions to neurology

* Tel.: þ91 832 249 5085; fax: þ91 832 245 8728. E-mail address: [email protected]. 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.04.005

services at tertiary-care referral centres and 0.06% of all admissions to the medical service of a general hospital [4e6]. Clinically recognised ODS may be on the rise possibly due to the inability of some patients to tolerate rapid increase in sodium levels [2]. Magnetic resonance imaging (MRI) has enabled ante-mortem diagnosis of ODS, and has expanded its clinical spectrum with detection of many mild, atypical or asymptomatic cases [7e11]. Recent data suggest that ODS is under-diagnosed: 0.3e1.1% of consecutive unselected autopsies showed evidence of unsuspected CPM and the proportion was as high as 9.8e29% in liver transplant recipients and 9.5% in asymptomatic patients with chronic liver disease [12e17]. Autopsy findings and retrospective clinical correlation, as well as studies in living patients using MRI suggest that many, if not most, cases of ODS are clinically asymptomatic, possibly due to the small size of the lesion [2,12,13,18,19]. Thus the true incidence of ODS is unknown: it has been suggested that this rate may be most accurately estimated by autopsy series [13]. The fact that ODS, despite the striking pathological abnormalities seen, was not recognised before the 1950s suggests that it is an iatrogenic disease: the consequence of the widespread use of intravenous fluid therapy at that time following the introduction of plastic tubing [16,20]. Recent evidence suggests that the distinctive clinical, pathological, and radiological features of ODS may not be as characteristic as once believed, and that the clinical syndrome of ODS may be expanding to include a wider variety of patients [16]. Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) are but two

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A. de Souza / Parkinsonism and Related Disorders 19 (2013) 709e716

aspects of the same disease. Initially considered a distinct entity from CPM, EPM is now well-recognised as the manifestations of ODS occurring in the brain in locations other than the pons. CPM and EPM have the same pathology, associations and time course but show differing clinical features [20]. Although the classic description of ODS includes the central pontine myelinolytic lesion affecting the transverse pontocerebellar fibres and the long rostrocaudal tracts [21], histological examination failed to show a pontine lesion e hitherto the sine qua non of ODS e in 21% of cases of ODS. Extrapontine sites were involved in 53% of patients in the same autopsy series [22]. These involve predominantly subcortical grey matter nuclei, rather than white matter tracts, and include the cerebellum, putamina, caudate nuclei, thalami, lateral geniculate bodies, and fronto-temporal cortex or subcortical white matter. Other locations include the cerebellar peduncles, fornix, hippocampi and external capsules [2,5,7,21,23e25]. Initial reports found the cerebellum to be most frequently involved (33e55%), followed by the thalami and striatum (34% each) which characteristically spares the globus pallidus although rare cases of presumed myelinolysis restricted to the pallidum have been reported [2,7,22,23,26,27]. Recent papers have highlighted the high incidence of striatal lesions in ODS (76e100%) which may be more common than pontine involvement [5,6]. This topographical localisation is responsible for the clinical syndrome in the individual patient, and is useful to make a diagnosis. A variety of movement disorders result from striatal involvement in ODS [2,5,22e24] (Table 1). Early reports stressed the rarity of EPM: in many series, as few as 10% of patients with CPM had concomitant EPM [15,17,20,23,28]. However, in other published series, the proportion of EPM in ODS detected on imaging or at autopsy varies from 22 to 80% [2,5,7,12,19,22]. In specific situations, for example liver transplant recipients, EPM probably occurs in a higher proportion of patients than is currently recognised, but is not adequately investigated. It may be responsible for many cases of “acute encephalopathy” following liver transplantation, which are not adequately investigated and no definite cause is found [7]. Similarly, presentation of EPM as a diffuse encephalopathy may lead to confusion with persistent hyponatraemic encephalopathy, and thus to its underdiagnosis. Progression of CPM to involve extrapontine locations on subsequent MRI or autopsy has also been demonstrated [29]. The high incidence of EPM in recent studies has been attributed to better quality MRI, use of diffusion-weighted imaging, or to the fact that MRI done later in the course of the illness would detect more lesions [5]. ODS occurs in the setting of significant medical illness: hyponatraemia was associated with 21.5% of all ODS cases reported between 1986 and 2002 with 39% were associated with alcohol use [2,18]. Myelin destruction follows osmotic stress resulting from a failure to compensate for rising plasma tonicity: oligodendrocytes are most susceptible to physical damage and triggering of apoptosis following shrinkage [7,20,22]. The end result is circumscribed spheroidal areas of demyelination, loss of oligodendrogliocytes, and astrocytic and microglial hyperplasia without inflammation or destruction of neuronal bodies or axons [2,7,9,10,17,19,23,29]. The predilection for certain areas such as the central pons may be due to the inflexible “grid-like” arrangement of oligodendrocytes in these regions, rendering them prone to osmotic damage during electrolyte correction [5,30]. ODS is also more common in sites where grey and white matter interdigitate, and may be due to the chemical effect of endothelial myelinotoxic factors entering the more vascular grey matter from blood (particularly after correction of dyselectrolytaemia as the bloodebrain barrier is often disrupted at this time) [11,18,26,28,31] or the mechanical effects of vasogenic oedema or rapid local shifts in osmolarity as ions diffuse across the bloodebrain barrier [7,17,24,28,29]. Detailed discussions of factors predisposing to ODS and pathogenesis are available [2,6,7].

2. Movement disorders due to ODS Clinical or radiologic evidence of neurologic damage due to ODS begins 0.5e7 days after osmotic shifts occur, but may be delayed by as long as 16 days [19,23,31,32]. Symptoms may be mild and a high degree of suspicion is necessary to make the diagnosis [11]. Patients generally e but not in all cases e exhibit a biphasic course in which the first set of symptoms are due to a nonlocalising encephalopathy due to hyponatraemia, and a period of relative improvement (the “lucent interval”) lasting one to seven days separates this from the subsequent development of ODS [5,6,19,22,29,33]. The disease has been characterised as a prominent neuro-behavioural disorder due to white matter disease in the pons and elsewhere in the brain [2]. CPM is classically associated with severe tetraparesis, bulbar palsy, coma or locked-in state, and less commonly dysarthria, dysphagia, ophthalmoplegia, or facial paresis [7,8,10e12,17,23,26,34]. The varied topographic localisation of lesions in EPM leads to many different clinical symptoms: altered consciousness, confusion, emotional lability, ataxia, tremor, myoclonus, akinetic mutism, catatonia, dysautonomia, quadriparesis and others with later progression to dystonia, choreoathetosis or parkinsonism which is often poorly responsive to levodopa (Table 2) [2,15,16,19,20,35e39]. Early reports stressed the rarity of extrapyramidal symptoms in ODS, often thought to be masked by corticospinal or brainstem dysfunction, but noted delayed development of tremor, rigidity, bradykinesia, dystonia, choreoathetosis and released reflexes which manifested 10e150 days after ODS begins [20,23,39,40]. Such delayed clinical features are due to ineffective neuronal reorganisation or repair, and may be progressive and refractory to treatment [19,20,35,36,38,39]. These delayed movement disorders may be analogous to delayed dystonia seen with static encephalopathy, and are likely due to neuronal reorganisation with new synaptic connections, delayed death of affected neurons, denervation supersensitivity, trans-synaptic degeneration of neural structures or ongoing myelinolysis [39]. Patients may evolve through a variety of clinical features: from the initial spastic tetraparesis to an akinetic-rigid state to choreoathetosis or dystonia (Video) [7,20,39,41]. Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.parkreldis.2013.04.005. However, extrapyramidal syndromes are now well recognised as common early manifestations of ODS: 44e50% of patients with ODS had parkinsonism at onset, and a further 16% developed delayed symptoms e either parkinsonism, choreoathetosis or dystonia [5,6]. Hypokinesia, cogwheel rigidity and tremor were present with varying combinations and severity. Tremor has been reported in 33% of all cases of ODS [11], and an anecdotal report of cortico-basal syndrome is available. The latter patient presented with asymmetric cogwheel rigidity and bradykinesia with ideomotor apraxia and pyramidal signs, but with only CPM on MRI. The authors were unable to explain the presence of cortical signs or continued progression with a single pontine lesion [38]. Generalised dystonia due to striatal myelinolysis has been reported in patients with hypoadrenalism due to sellar tumours [42]. Akinesia, catatonia, encephalopathy with altered consciousness, opsoclonus, emotional lability, and gait disorders have also been attributed to striatal involvement in other reports [2,15,16,19,20,37e39]. Due to the combination of hypo- and hyper-kinetic movement disorders seen in EPM it has been postulated that striatal lesions result in variable disruption of both direct and indirect striato-pallidal pathways. Both types of movement disorders can be seen due to alterations in the rate or pattern of activity in thalamic, pallidal, subthalamic or cortical neurons [20]. EPM is a rare cause of secondary parkinsonism, which is thought to result from a relative dopamine deficiency due to reduction of

A. de Souza / Parkinsonism and Related Disorders 19 (2013) 709e716

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Table 1 Reported cases of movement disorders due to ODS. Ref

Ref Author

[6,41] 6,41 de Souza

[55] [43] [19]

55 43 19

Imam Toft Odier

[25] [29] [46] [22] [42]

25 29 46 22 42

Gujjar Pietrini Shin Post Srimanee

[37] [4]

37 4

Wu Bhoi

Year Age Sex CPM EPM: EPM: Other striatum sites

Imaging Autopsy/ HypoNaþ Rapid Timing Type Biopsy osmotic of MD* of MD** shift

2012 50 62 45 89 65 2012 30 2011 42 2010 45 66 62 50 2010 40 2009 61 2009 36 2009 63 2009 35 24 2009 48 2007 44

M F F F M M F M F F M F F M F M M F M

þ e e e e e e þ þ þ þ e þ þ e e e e þ

þ þ þ þ þ þ e þ þ e þ þ þ þ þ þ þ þ þ

e e e e Thalamus Thalamus Midbrain e e e e Thalamus Thalamus e e e e e Thalamus

MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI

e e e e e e e e e e e e þ e e e e e e

þ þ þ þ þ þ þ þ þ e þ þ þ þ þ þ þ þ þ

þ þ þ þ þ þ ? þ þ e þ e e þ þ þ e þ e

A A, D A A A A A, D A A A A A A A A A A D A

P P, later D P,D P P P P, later D P P Dyskinesia P, D, M P, T T P P D D P D, P, T

62 36

M M

þ þ

þ þ

e e

þ þ

e e

A A, D

53

F

þ

þ

Periventricular MRI Thalamus, MRI midbrain ? MRI

e

þ

þ

D

P P, later D, T P, D

55 53 45 45 61 41 37 50

M F F M F F F M

e þ þ þ e þ þ þ e þ

MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI

e e e þ e e e e e e

þ þ þ þ þ þ þ þ þ þ

þ þ þ e þ þ þ ? þ þ

A A A A D A A A A A

MRI

e

þ

þ

A,D

[56] [57] [35] [38] [23] [58] [34] [59] [45]

56 57 35 38 23 58 59 60 45

Twardowschy Gupta Ho Shamim Sajith Okada Pangariya Tison Koussa

2007 2007 2006 2006 2006 2005 2005 2004 2003

59

F

þ þ þ þ þ e e þ þ e

[20]

20

Seah

2002 60

F

þ

þ

e e Thalamus e e e e Midbrain e Periventricular, thalamus e

[44] [40] [28] [36]

44 40 28 36

Kim Sullivan Nagamitsu Seiser

2002 2000 1999 1998

61 56 11 51

F M F F

e þ e þ

þ þ þ þ

þ e Thalamus Thalamus

MRI MRI MRI MRI

e e e e

þ þ þ þ

þ þ þ e

A A A A, D

[60] [61] [62]

61 62 63

Salvesen Federlein Tomita

1998 1998 39 1997 53

F F M

e þ e

þ e þ

e e e

MRI MRI MRI

e e e

þ þ þ

þ þ þ

A A A

P P P, D P, T, M CBS, D P P P C, D P, T, catatonia T,M, later P, D, C P P, T P P,M, later D P C P, D

[63] [64] [39]

64 65 39

Pradhan Sadeh Maraganore

1995 39 1993 52 1992 51

M F F

þ þ þ

e e þ

Thalamus e e

MRI MRI

e e e

þ þ þ

e þ þ

A D D

P P D

F F F M

þ þ þ þ

þ þ e e

[65] [66]

66 67

Wu Hirano

55 63 1992 47 1992 43

[67]

68

Salerno

1992 44

F

þ

e

e e Midbrain, thalamus e

[68] [69] [70] [71] [72] [73]

69 70 71 72 73 [74]

Niwa Tinker Thompson Grafton Dickoff Stam

1991 1990 1989 1988 1988 1984

M F F M M

þ þ þ þ þ þ

þ e e e þ e

Subcortical e e e e e

39 66 52 57 50

MRI MRI MRI MRI

e e e e

þ þ þ þ

þ þ þ þ

D A D A

P P,D D P

MRI

e

þ

þ

A, D

P, later D

MRI MRI MRI MRI MRI CT

e e e e e e

þ þ þ þ

þ þ þ þ

A A D D A A

P P D D P P, T

Treatmenta

Efficacyb Video

LD, amantadine LD, amantadine LD, anticholinergic LD LD LD LD, ropinirole ? ? ? ? Pramipexole e LD ? ? LD, anticholinergic LD LD, anticholinergic, clonazepam, baclofen Anticholinergic ?

þ þ þ e  þ þ þ ? ? þ þ e þ þ e þ þ þ

e þ e e e e e e e e e e e e e e e

þ þ

e e

LD, Botulinum toxin e e Anticholinergic ? ? LD, baclofen e ? ? Bromocritpine



e

þ þ þ þ e þ þ þ ? þ

e e e e e e e e e e



e

þ þ þ 

e e e e

þ þ e

e e e

þ þ e

e e þ

? ? þ þ

þ þ e e

e

e

? þ ? e ? ?

e e e e

LD, baclofen, antichol LD LD LD LD, tiapride, perphenazine ? e LD, amantadine, pergolide, bromocriptine anticholinergic, ? LD Anticholinergic, baclofen ? ? Anticholinergic LD LD, haloperidol, clonazepam ? LD ? LD, anticholinergic ? ?

e

e

HypoNaþ: hyponatraemia. *MD: movement disorder; A: acute onset; D: delayed onset. **P: parkinsonism; D: dystonia; T: tremor; M: myoclonus; C: choreoathetosis; CBS: cortico-basal syndrome. a LD: levodopa. b “e”: no improvement; “”: minimal improvement; “þ”: better than minimal improvement; “?”: not specified.

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Table 2 Clinical features due to ODS affecting the basal ganglia. See the text for references. Early manifestations

Late manifestations

Symmetric akinetic-rigid state Dystonia Tremor Myoclonus Corticobasal syndrome Catatonia Opsoclonus Gait disorders Apathy, akinetic mutism Primitive reflexes Dysarthria, mutism, dysphagia

Dystonia Parkinsonism Chorea, choreoathetosis Gait disorders Subcortical dementia Depression, emotional lability, paranoia, disinhibition

the presynaptic striatal dopamine transporter and of dopamine receptors on myelinated fibres in the striatum. A symmetric akinetic-rigid state with or without significant tremor and/or postural dysfunction is the commonest movement disorder in many large series of patients with ODS [5]. Although the midbrain has been identified as a key area for the development of parkinsonism, most reported cases show lesions involving the striatum: only recently has a case of presumed myelinolysis involving the substantia nigra been reported [43]. The pathogenesis of the parkinsonian syndrome is not fully clear [22,44]. Structural imaging with MRI is unable to delineate the severity of involvement of the nigrostriatal dopaminergic pathway in individuals with EPM with parkinsonism and does not correlate well with clinical features [37]. Studies using single-photon emission computed tomography (SPECT) have been used to study the functional status of the substantia nigra and its dopaminergic neurons in patients with parkinsonism due to ODS affecting the caudate and putamen. These have shown a severe reduction in the density of the presynaptic striatal dopamine transporter, suggesting osmotic damage to the nigrostriatal pathway in addition to local striatal pathology in EPM affecting the postsynaptic dopaminergic receptor. Involvement was more severe in presynaptic neurons, and asymmetry of clinical signs correlated well with asymmetric reduction in uptake of the radiotracer ligand [37,43,44]. Increased levels of dopamine metabolites like homovanillic acid in the cerebrospinal fluid of a patient with acute parkinsonism due to EPM without CPM suggest that the disease causes a reduction of dopamine receptors on myelinated fibres in the striatum. This leads to decreased function of the striatonigral negative feedback loop and of inhibitory autoreceptors thereby enhancing dopamine and serotonin secretion, with a consequent rise in cerebrospinal fluid levels of dopamine metabolites. The relative dopamine deficiency would likely explain the akinetic-rigid syndrome seen in EPM. Such a model would not necessarily implicate midbrain or pontine involvement [28]. Dopaminergic therapy, principally levodopa but also pramipexole, leads to clinical improvement similar to that seen in idiopathic Parkinson’s disease, by activating the remaining dopamine receptors and ameliorating the relative dopaminergic deficit due to reduced presynaptic nigrostriatal outflow [16,28,37,44]. The CSF level of homovanillic acid should then fall to normal levels, as has been demonstrated by Nagamitsu and co-workers [28]. Persistent encephalopathy seen in patients with only striatal involvement may be due to disruption of frontal-subcortical cognitive circuits or due to small myelinolytic lesions in or near the cortex which were not detected by MRI. Even patients with isolated CPM show cognitive dysfunction: this may be due to concomitant EPM, missed by MRI, or to disruption of corticosubcortical circuits or the ascending reticular activating system due to pontine dysfunction [2,19]. That striatal myelinolysis is often associated with depression serves to reiterate the role that the deep

grey matter plays in the control of affect and emotion. Neurobehavioral and cognitive symptoms in EPM may also be due to arcuate u-fibre damage at the cortico-subcortical junction [2]. Catatonia has rarely been reported, either as a brief episode lasting days before resolving and being replaced with parkinsonian features, or two weeks after onset of ODS following the resolution of spastic tetraparesis [7,45]. Delusions, depression, emotional lability, disinhibition, paranoia, rage, disorientation, apathy, and mutism are usually due to disruption of the frontal-subcortical circuits running through the basal ganglia, and often improve significantly [2,16,20,31]. Recovery is often good in patients who survive the initial illness, but may be incomplete, mimicking a subcortical dementia (mild affection of intelligence, language relatively spared, problems with executive function and with retrieving memories). These behavioural symptoms may cause significant disruption during the acute illness and during the process of recovery [2]. Primitive reflexes are often a prominent feature, even in the absence of frontal cortical or subcortical white matter lesions, and may be possibly due to damage to the frontal-subcortical cognitive and motor circuits by the striatal lesions of EPM that produced “release” of these reflexes [6]. Most patients with ODS have severely reduced speech output with hypokinetic dysarthria or nonspecific slurring of speech even in the absence of pontine lesions. Decreased orobuccolingual movements, speech tremor and poor speech output have all been attributed to striatal dysfunction in EPM [23]. Mutism and dysphagia have been noted to occur in 32% of patients with ODS even in the absence of bulbar palsy or quadriparesis [5,34]. 3. Role of MRI By 1972, only 2 of 100 reported cases of ODS had been diagnosed ante-mortem [10]. The modern scenario is very different, thanks to the advent of neuroimaging. MRI is decisive in making a diagnosis of ODS, helping to uncover new cases, delineate the extent of and trace evolution of the lesion, and correlate progression or regression with clinical features [8]. It is useful to detect asymptomatic or mild ODS cases [2,10,16]. Although clinical features of ODS usually precede MRI changes e indeed MRI may take weeks to become abnormal e rarely a typical imaging picture can be seen up to a week before onset of ODS [5,8,11,16,19,24,31,46]. Typically CPM produces a trident-shaped lesion in the basis pontis from the pontomedullary junction to the midbrain sparing peripheral tissue including the corticospinal tracts and ventrolateral tegmentum [10,23]. No correlation exists between clinical features and MRI findings in CPM [24,47]. The lesions of EPM are symmetric and contemporaneous in age at various sites [7]. Striatal and thalamic lesions are symmetric, T2- and FLAIR-hyperintense, and T1hypointense without contrast enhancement [5,16,37]. In one series lesions in the basal ganglia were seen in two-thirds of patients with ODS, while in another, all patients showed striatal lesions [5,6] (Fig. 1). Since ODS is due to disturbed fluid and osmotic balance, it is not surprising that DWI abnormalities along with restriction seen on ADC maps may be useful for early diagnosis. The disease may not be visible on other sequences even as late as 12 days after onset [7,15,21,37,46,48]. Low ADC values early on are due to cytotoxic oedema and a rise in the volume of intracellular fluid as compared with extracellular volume, producing restriction of movement of water molecules. This restriction may also help in differentiating ODS from multiple sclerosis, acute disseminated encephalomyelitis or certain tumours [15,48,49]. Restriction may increase on subsequent imaging studies but is not seen beyond three weeks after onset of ODS: high signal on DWI without restriction may be due to a “T2 shine-through” effect or bloodebrain barrier breakdown [15,21].

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Fig. 1. (A) MRI of the brain on 1.5 T system of a patient with symmetric parkinsonism and subcortical dementia due to combined pontine and extrapontine myelinolysis. The axial T2-weighted (T2W) and FLAIR images show hyperintense lesions in the central pons, putamina and both caudate nuclei. The DWI (b ¼ 1000) and ADC images show restricted diffusion in the striatal lesions. (B) MRI of the brain on 0.2 T system of a patient with symmetric parkinsonism and dystonia with later depression due to extrapontine myelinolysis. The axial FLAIR images and coronal T2W images show hyperintense lesions in the thalami, putamina and both caudate nuclei. Pons was normal (not shown).

Even though it is very sensitive in detecting lesions of ODS, MRI may miss small lesions found later at autopsy [19,31]. Repeated imaging may detect involvement not seen earlier, and therefore should be done at around two weeks’ interval in all patients with suspected ODS [5,19,46,47]. Functional imaging has infrequently been employed in studying ODS: 18-fluorodeoxyglucose positron emission tomography showed bilateral caudate and putaminal lesions [50] with evidence of early hypermetabolism and late hypometablism within the demyelinating lesions [51]. The authors speculated that active microglia and reactive astrocytes were the main cause of the increased glucose metabolism. 4. Diagnosis ODS is easily suspected in the typical clinical setting where a patient with recent or ongoing electrolyte disturbance, malnutrition, alcohol abuse, recent liver transplant, severe systemic illness or a combination of these develops acute quadriparesis, parkinsonism or coma. However the protean manifestations listed above as well as the extensive list of conditions known to predispose to ODS necessitate a high index of suspicion, particularly when an individual fails to recover as expected or develops new “psychiatric symptoms” after a severe illness [7]. Although hyponatraemia is the commonest factor precipitating ODS, it is by no means always present. The clinical picture is often confounded by critical illness, neuromuscular blockade or sedative administration [15]. The acute onset of a symmetric akinetic-rigid state with minimal tremor and moderate to marked axial rigidity; dystonia; seizures; worsening of consciousness in the appropriate clinical setting should prompt consideration of EPM. Diagnosis in the pre-MRI era was nearly always postmortem [10], and even today arriving at a diagnosis of ODS

without the assistance of MRI remains difficult. However a normal MRI does not rule out ODS: as mentioned above, clinical symptoms and signs precede MRI changes - often by weeks - and a repeat imaging study should be obtained after about 15 days if the first does not confirm the clinical impression of ODS. The MRI protocol should include DWI, T2-weighted and FLAIR images. Contrast administration is unhelpful. Cerebrospinal fluid examination is warranted only to rule out other possible diagnoses. Brainstem auditory evoked responses were used for diagnosis of CPM before CT scan became available as they may show a prolonged interpeak latency between waves I and V, but this is neither sensitive nor specific [18]. As the clinical manifestations of ODS vary according to the topography of the myelinolytic lesions, a wide differential diagnosis needs to be considered. Vertebrobasilar stroke, encephalitis or postencephalitic sequelae, multiple sclerosis, acute disseminated encephalomyelitis, drug or toxin exposure, prion disorders, neurodegenerative disorders, or pontine tumours all produce similar clinical and/or imaging findings. Symmetric involvement of the deep nuclei on MRI can be seen in toxic, hypoxic-ischaemic or other metabolic encephalopathies [23]. 5. Management and prognosis Prevention of ODS is of paramount importance. CPM has been associated with low, high or normal sodium levels [29] but hyperosmolarity or rapid osmotic shifts are more important in the pathogenesis of myelinolysis than the absolute sodium level. Concomitant malnutrition, alcohol or drug abuse, Addison’s disease, hypoxia, immunosuppression, hypoglycaemia, hypokalaemia or azotaemia all increase the likelihood of developing ODS after rapid sodium correction [22,23,52]. Patients with very low serum

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sodium levels (<105 mmol/L) [47] and those with sodium levels <120 mmol/L for >48 h treated with hypertonic saline infusions to achieve rapid or over-correction are at greatest risk [10,17]. It is well established that rapid correction following early aggressive treatment is linked to ODS, and to persistent brain dysfunction after sodium levels return to normal [13,47]. The optimal rate of correction of sodium is still a matter of controversy: correction is affected by the severity of hyponatraemia and its symptoms, and it is not easy to maintain an optimal rate of correction throughout. Although acute hyponatraemia mandates aggressive and rapid treatment and rarely causes ODS [17], in case of any doubt it is safest to assume that the electrolyte disturbance has been present for more than 48 h, and to proceed with due caution particularly in malnourished patients [7,32]. Early studies showed that a rise in sodium levels by >12 mmol/L day or >25 mmol/L in 48 h was a risk factor for ODS [26,28,29]. The recommended maximum rate of correction was subsequently lowered to 10 mmol/L day [19,33,37] but even this rate may be too high [26,29]. Current data indicate that the risk of ODS increases if sodium levels rise >8 mmol/L day [7,52] but ODS occurs even with optimal rates of correction [14,29,52]. This may be due to comorbid conditions, or may be due to the role played by the absolute sodium level rather in addition to the rate of correction [28,52]. To prevent this, some authors recommend even slower correction (<12 mmol/L rise in 48 h or <0.5 mmol/L rise per hour [18,29]), and avoidance of correction to normal or elevated sodium levels within 48 h (i.e. maintenance of mild hyponatraemia) [7,31,47]. Hypokalaemia was the only electrolyte disturbance noted in the original paper describing CPM [1], and is often noted in patients who eventually develop ODS [29]. It is not often appreciated that normalisation of potassium levels before sodium correction commences may minimise the risk of ODS [10]: a recent series showed that adequate correction of hypokalaemia was not carried out until after symptoms of ODS began [6]. No specific therapy exists for ODS [10]. Thyrotropin releasing hormone, plasma exchange, methylprednisolone, and intravenous immunoglobulin have all been anecdotally effective but no randomised trial has ever been carried out, and the mechanism of benefit is not known. Only supportive care may be justified in the absence of confirmed efficacy of the above treatment [11]. Steroids are recommended on the basis of rat experiments in which dexamethasone prevented the development of ODS [33]. They prevent microglial activation stabilising the bloodebrain barrier and suppressing cytokine secretion. Therefore it has been proposed that steroids be given just before sodium correction in severely hyponatraemic patients [2]. Although outcomes from ODS are reported to improve with steroid therapy, particularly in EPM, the absence of florid inflammation on histological examination casts into doubt the utility of immunomodulatory treatment [29,53]. ODS may be prevented by reinduction of mild hyponatraemia if initial symptoms appear, and patients at risk of ODS after aggressive osmolar correction may be rescued with appropriate fluid management before brain injury has occurred [7,16,33]. The movement disorders of EPM represent a treatable manifestation of the osmotic demyelination syndrome in that a rewarding symptomatic improvement can occur with dopaminergic treatment in those with parkinsonian features [7]. Although delayed movement disorders respond poorly to drug treatment [20], in general parkinsonism resulting from acute ODS shows a good response to levodopa [7,28]. Levodopa is thought to alleviate symptoms by activating the remaining dopamine receptors in the striatum. Dopamine agonists like pramipexole are also reported to benefit patients with EPM who had a striatal presynaptic dopamine transporter defect [25]. The presynaptic dopaminergic defect in EPM resembles that in Parkinson’s disease e often with similar patterns of asymmetry in clinical and imaging data e and explains

the good response to levodopa seen in both conditions [37,44,45]. Clinical improvement has been shown to correspond to normalisation of radiotracer ligand uptake on serial SPECT studies after initial SPECT showed severely reduced presynaptic uptake [37]. Hitherto commonly believed to have a very poor prognosis [8,52], ODS is more benign than previously thought [15]. The outcome is not inevitably poor and the disease is no longer as devastating as it was 50 years ago [16,52]. This is due to early recognition using MRI, better knowledge of the pathophysiology of electrolyte disorders, more precise fluid management, and better intensive care techniques [16]. Most patients survive if secondary complications due to debility like aspiration, sepsis or pulmonary thromboembolism can be avoided [2]. From 90 to 100% mortality at three months in earlier series [10,11,54], with modern intensive care almost half the patients have a good outcome with 28e39% recovering completely, and a further 16e34% becoming independent for ADL [5,11,19,54]. In paediatric series, 94% of cases prior to 1990 and only 7% of cases from 1990 onward resulted in patient mortality [3]. Recovery is usually seen early but may be delayed by as much as four years [22,23]. Hospital stay averaged 28e32 days [5,6]. Prompt improvement may be due to selective myelin damage with relative sparing of axons [23] or reversal of neurotransmitter block in the pons after resolution of vasogenic oedema, while delayed recovery has been attributed to synaptic plasticity [34]. Good nursing care and aggressive rehabilitative measures are therefore essential, given the prospect of a good recovery despite an initially severe deficit [10,19]. As the disorder is of diverse aetiologies and often associated with severe medical illness, outcomes vary [19]. Attempts to describe prognostic factors in patients with ODS have been largely unsuccessful: outcome is not correlated with clinical features or the size of the lesion on MRI [5,7,8,16,42,54]. The size of the lesion on MRI is not proportional to severity or outcome [8,42]. The abnormal signal intensity changes usually persist, although normalisation of the MRI over a period of up to four years has been reported [16,22,31]. Although some authors have suggested that patients with normal ADC maps at an early stage have better recovery [46], this was not confirmed in other series [5,6]. However, some authors have suggested that the presence of altered consciousness or seizures had a detrimental effect on the outcome [6] and were indicative of potential mortality, in contrast to other presentations like ataxia which had a better prognosis [19]. ODS arising as a complication of severe systemic illness, associated liver dysfunction, low sodium and potassium levels at admission, absent “lucent interval”, and severe disability at admission and discharge were predictive of poor outcome [5,6,16]. In keeping with the recent trends towards improved survival in ODS, a retrospective series of 76 paediatric cases of ODS over 50 years identified the decade in which the case was reported as the strongest predictor of outcome, followed by sodium dysregulation and dehydration [3]. Even in patients who survive the initial illness, neuropsychological abnormalities suggesting frontal-subcortical dysfunction persist in most and may be the only significant residuum of neurological damage in as many as a third of survivors, precluding a return to a normal life [19]. The commonest neurological sequelae in survivors of EPM are global cognitive defects, extrapyramidal or cortico-bulbar disorders [45]. Patients with delayed progression of extrapyramidal symptoms have a poor prognosis due to ineffective or haphazard reorganisation and repair of neural structures [20]. 6. Conclusion The widespread use of MRI has resulted in increasing recognition of the association of ODS e in particular EPM e with movement disorders. Parkinsonism and less commonly dystonia are

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often noted in the initial evaluation of patients with EPM, while those surviving the acute illness may manifest delayed dystonia, parkinsonism, choreoathetosis and other movement disorders. Such delayed movement disorders are likely to become more common as improvements in intensive care techniques lead to increased survival of acutely ill patients with ODS. Parkinsonism often shows a salutary response to dopaminergic therapy, while delayed manifestations may be refractory to treatment and may progress despite the physician’s best efforts. Ethical approval The patient depicted in the video provided written informed consent to being filmed and for the recording to be used for teaching and research. The hospital ethics committee of Goa Medical College approved the article. Funding None. Conflict of interest None. References [1] Adams RD, Victor M, Mancall EL. Central pontine myelinolysis. Arch Neurol Psychiatry 1959;81:154e72. [2] Kleinschmidt-DeMasters BK, Rojiani AM, Filley CM. Central and extrapontine myelinolysis. then and now. J Neuropathol Exp Neurol 2006;65:1e11. [3] Ranger AM, Chaudhary N, Avery M, Fraser D. Central pontine and extrapontine myelinolysis in children: a review of 76 patients. J Child Neurol 2012;27: 1027e37. [4] Bhoi KK, Pandit A, Guha G, Barma P, Misra AK, Garai PK, et al. Reversible parkinsonism in central pontine and extrapontine myelinolysis: a report of five cases from India and review of the literature. Neurol Asia 2007;12:101e9. [5] Kallakatta RN, Radhakrishnan A, Fayaz RK, Unnikrishnan JP, Kesavadas C, Sarma SP. Clinical and functional outcome and factors predicting prognosis in osmotic demyelination syndrome(central pontine and/or extrapontine myelinolysis) in 25 patients. J Neurol Neurosurg Psychiatry 2011;82:326e31. [6] de Souza A, Desai PK. More often striatal myelinolysis than pontine? A consecutive series of patients with osmotic demyelination syndrome. Neurol Res 2012;34:262e71. [7] Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry 2004;75:iii22e8. [8] Laubenberger J, Schneider B, Ansorge O, Götz F, Häussinger D, Volk B, et al. Central pontine myelinolysis: clinical presentation and radiologic findings. Eur Radiol 1996;6(2):177e83. [9] Hadfield MG, Kubal WS. Extrapontine myelinolysis of the basal ganglia without central pontine myelinolysis. Clin Neuropathol 1996;15:96e100. [10] Kiley MA, King M, Burns RJ. Central pontine myelinolysis. J Clin Neurosci 1999;6:152e7. [11] Musana AK, Yale SH. Central pontine myelinolysis: case series and review. Wis Med J 2005;104:56e60. [12] Razvi SSM, Leach JP. Asymptomatic pontine myelinolysis. Eur J Neurol 2006;13:1261e3. [13] Newell KL, Kleinschmidt-DeMasters BK. Central pontine myelinolysis at autopsy; a twelve year retrospective analysis. J Neurol Sci 1996;142:134e9. [14] Huq S, Wong M, Chan H, Crimmins D. Osmotic demyelination syndromes: central and extrapontine myelinolysis. J Clin Neurosci 2007;14:684e8. [15] Kumar S, Fowler M, Gonzalez-Toledo E, Jaffe SL. Central pontine myelinolysis, an update. Neurol Res 2006;28:360e6. [16] Brown WD. Osmotic demyelination disorders: central pontine and extrapontine myelinolysis. Curr Opin Neurol 2000;13:691e7. [17] Luzzio C. Central pontine myelinolysis. Online, http://emedicine.medscape. com/article/1174329-overview; August 26, 2009 [accessed 14.07.10]. [18] Lampl C, Yazdi K. Central pontine myelinolysis. Eur Neurol 2002;47:3e10. [19] Odier C, Nguyen DK, Panisset M. Central pontine and extrapontine myelinolysis: from epileptic and other manifestations to cognitive prognosis. J Neurol 2010;257:1176e80. [20] Seah ABH, Chan LL, Wong MC, Tan EK. Evolving spectrum of movement disorders in extrapontine and central pontine myelinolysis. Parkinsonism Relat Disord 2002;9:117e9. [21] Ruzek KA, Campeau NG, Miller GM. Early diagnosis of central pontine myelinolysis with difusion-weighted imaging. Am J Neuroradiol 2004;25:210e3.

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