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Primary sleep disorders can cause long-term sleep disturbance in patients with autoimmune mediated limbic encephalitis
Clinical Neurology and Neurosurgery 115 (2013) 1079–1082
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Primary sleep disorders can cause long-term sleep disturbance in patients with autoimmune mediated limbic encephalitis Kirstie N. Anderson a,∗ , Thomas P. Kelly b , Timothy D. Griffiths b a b
Department of Neurology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom Institute of Neuroscience, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom
a r t i c l e
i n f o
Article history: Received 27 September 2011 Received in revised form 28 October 2012 Accepted 31 October 2012 Available online 21 November 2012 Keywords: Limbic encephalitis Sleep apnoea Restless legs
a b s t r a c t Objectives: Antibody mediated limbic encephalitis causes a sub acute encephalopathy with an amnestic syndrome, seizures and often an affective prodrome. Sleep disturbance including abnormal dream sleep and insomnia are described in a percentage of long-term survivors but there are very few detailed assessments of sleep disturbance in patients beyond the acute phase of illness. The objectives of this study were to understand the causes of sleep disturbance in the long-term survivors of antibody mediated limbic encephalitis. Patients and methods: We screened twelve patients under long-term follow up with sleep questionnaires and went on to perform detailed sleep studies (polysomnography) in those who reported sleep disturbance. Results: Two were found to have persistent, severe central and obstructive sleep apnoea and two others to have restless legs and periodic limb movements of sleep. Conclusions: This highlights the need to investigate sleep disturbance in this group of patients. Effective treatments may be available to improve quality of life and daytime function. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Autoimmune or paraneoplastic limbic encephalitis is increasingly recognised as a cause of sub acute encephalopathy with seizures and an amnestic syndrome [1]. The identification of antibodies to anti-Ma, anti-Hu, the voltage gated potassium channel (VGKC), the N-methyl-d-aspartate receptor (NMDA-R) and the AMPA receptor has highlighted the potential for immunotherapy for these disorders [2–4]. Additionally, a number of patients have a similar clinical presentation but do not have any of the currently described antibodies on clinical testing, although understanding of immunological bases is rapidly evolving [5,6]. A number of patients have prominent and early sleep-wake disturbance as a feature of the acute illness. Hypersomnia with fragmented night sleep has been described in patients with anti-Ma encephalitis [7]. NMDA-R encephalitis patients present with reduced levels of consciousness often with hypoventilation requiring mechanical ventilation [4]. VGKC limbic encephalitis is associated with REM sleep behaviour disorder that can reverse upon successful treatment [8,9].
∗ Corresponding author. Tel.: +44 0191 2823833; fax: +44 0191 2825027. E-mail address: [email protected] (K.N. Anderson). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2012.10.031
A percentage of long-term survivors have persistent sleep disturbance, usually insomnia (Dalmau J, personal communication). There have been very few reports of any patients having subjective or objective sleep assessments following recovery from the acute illness when under long-term follow up. We screened patients with confirmed, non-infective limbic encephalitis who underwent detailed sleep assessments following recovery from their acute illness. Two patients had persistent, severe sleep apnoea causing sleep fragmentation, one of whom was successfully treated with non-invasive ventilation. Two patients had periodic limb movements of sleep and associated restless legs syndrome causing insomnia and daytime sleepiness which again responded to treatment. None of our patients had REM sleep behaviour disorder after the acute phase of the illness.
2. Methods 2.1. Patients All patients presented to the Neurology service at the Newcastle upon Tyne acute hospitals trust between 2001 and 2010. They were in-patients during the acute phase of the illness then followed up within the cognitive neurology clinic. All patients had a subacute amnestic syndrome and seizures. All patients underwent MRI scanning and EEG. All underwent
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K.N. Anderson et al. / Clinical Neurology and Neurosurgery 115 (2013) 1079–1082
cerebrospinal fluid (CSF) examination, and serological testing to exclude herpes simplex virus infection. All patients underwent an extended autoantibody screen, including thyroid-peroxidase antibodies and anti-neuronal antibodies. Associated cancer was sought on the basis of screening investigations and clinical follow-up of between 18 and 48 months. All patients underwent CT scanning of the chest, abdomen and pelvis which was negative. All patients had screening memory assessment during the acute presentation using Addenbrooke’s Cognitive Examination [10]. All patients received subsequent detailed assessment including assessment of current intellectual function (Wechsler Adult Intelligence Scale, 3rd Ed.) [11] and memory function (BIRT Memory and Information Processing Battery; BMIPB) [12]. Executive function was assessed using the Trail Making and Controlled Verbal Fluency Tests [13]. The neuropsychological assessment took place at 2 months and at intervals of 6 and 12 months thereafter. Measurement of serum VGKC-Ab titres was carried out within 4 weeks of admission and defined as negative if <100 pM. Measurement of serum NMDA-R antibodies was determined by a cell-based assay (assays performed at John Radcliffe Hospital, Oxford, UK).
He had a significant residual memory deficit on repeated testing that prevented him from resuming work. His only long-term medication at the time of assessment for sleep disturbance was clomipramine. MRI initially showed left hippocampal signal change but this resolved upon rescanning at 6 months. He had obvious sleep disturbance that had started after his acute illness and persisted up to the time of assessment with disturbed dream sleep and evidence of dream enactment, he was restless in bed with loud snoring and witnessed apnoeas. ESS was 13 and PSQI was 6. Polysomnography confirmed severe obstructive sleep apnoea (AHI 36.7, ODI 43.3) but showed no evidence of REM sleep behaviour disorder although he had multiple arousals from REM sleep coinciding with apnoeas and causing vocalisations and occasional limb movements. Weight remained unchanged before and after the acute illness with a normal body mass index of 24.3. He trialled CPAP but was unable to tolerate it. 3.2. Patient CD (Case 8 in Table 1)
Patients completed the Epworth Sleepiness Score (ESS) [14] and the Pittsburgh Sleep Questionnaire Inventory (PSQI) [15]. Ten patients with abnormal values in either questionnaire (ESS >10 and/or PSQI >5) were invited to attend the Regional Sleep Service for clinical interview followed by polysomnography. Polysomnography was performed using a standard procedure, including video recording, a sleep electroencephalogram (leads C4-A1 and C3-A2), bilateral eye movements, submental EMG, and bilateral anterior tibialis EMG to record any leg movements during sleep. Respiratory movements were detected with chest and abdominal bands measuring inductance, airflow was detected with nasal cannulae measuring pressure, and oxygen saturation of arterial blood was measured. Airflow limitation and changes in respiratory movement were used to detect increased upper-airway resistance. All respiratory events and sleep stages were scored according to standard criteria [16].
Patient CD, female 34 years presented with a 2-week progressive history of confusion, dysarthria and orofacial dyskinesia. Progressive complex partial and then generalised seizures led to intubation and ventilation on ITU. Prolonged central apnoeas were noted during the ITU admission. NMDA-R antibodies were initially positive and she was treated with plasma exchange, intravenous steroids and then oral steroids for a 6-month period, repeat antibodies were negative. Seizures and dyskinesia ceased but she had residual memory deficits and persistent sleep disturbance with fragmented night sleep and daytime fatigue. She had severe Restless Legs Syndrome based on the International Restless Legs Syndrome Society definition. ESS was 7 and PSQI was 6. Subsequent polysomnography excluded sleep apnoea but showed periodic limb movements of sleep (PLMI – 42). Symptomatic benefit was obtained with a combination of gabapentin and pramipexole with decreased sleep fragmentation but also improvement in anxiety and depression ratings (Becks anxiety index – BAI and Becks depression inventory – BDI) with neuropsychology assessment before and after intervention for sleep disturbance. Before treatment BAI = 32 severe anxiety, BDI = 35 severe depression. After treatment BAI = 17 and BDI = 15.
3. Results
3.3. Patient JB (Case 10 in Table 1)
Twelve patients with limbic encephalitis completed sleep questionnaires. Their clinical details and sleep questionnaire results are summarised in Table 1. All patients had their sleep assessments >3 months after their acute presentation. ESS scores ranged between 1 and 19 (mean 7.2) with 3 patients reporting a score ≥10. The PSQI scores ranged between 4 and 17 (mean 7.5) with 8 patients having scores in the abnormal range of ≥5. Ten patients with abnormal sleep scores were approached for polysomnography studies and 4 underwent polysomnography. The others declined further investigation. The polysomnography results are summarised in Table 2. Patients with abnormal polysomnography are discussed in detail below.
Patient JB, a slim male 36 years with no prior sleep disturbance presented in March 2007 with subacute agitation, focal and generalised seizures and apnoeas leading to intubation and ventilation. Upon extubation he had prominent orofacial dyskinesia. NMDA receptor antibodies were initially positive but negative after immunotherapy. He was treated with plasma exchange and then high dose intravenous methylprednisolone followed by oral steroids for the next 6 months. Addenbrookes cognitive estimate was 93/100 in June 2007 but he had persistent anxiety, eating disorder and low mood. He complained of troublesome insomnia from discharge and his wife noted frequent prolonged apnoeas and periodic limb jerks but no snoring. His polysomnography showed frequent prolonged central apnoeas (apnoea hypopnoea index 31.7/h, 18/h central apnoea) and associated arousals from sleep. He was successfully treated with an autoset CS device used to treat predominantly central apnoeas (apnoea hypopnoea index on autoset CPAP 5.2/h). A low dose of pramipexole was subsequently commenced to treat restless legs. He had subjective benefit in daytime function.
2.2. Sleep assessment
3.1. Patient WB (Case 3 in Table 1) Patient WB, male 60 years presented with acute headache, behavioural change anterograde amnesia and complex partial and generalised seizures over a 6-week period. He was initially treated with anticonvulsants and subsequently with intravenous and then oral prednisolone but steroids were not commenced until 4 months after acute presentation. A diagnosis of antibody negative limbic encephalitis was found, and there was no evidence of malignancy.
3.4. Patient CM (Case 11 in Table 1) Patient CM 36-year-old female presented with subacute confusion, behaviour change and complex partial and generalised
K.N. Anderson et al. / Clinical Neurology and Neurosurgery 115 (2013) 1079–1082
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Table 1 Clinical data and investigations. Patient
Age/gender
Presenting features
MRI
Antiepileptic medication
PSQI
ESS
1
56/M
Bilateral hippocampal high signal
PHT
2 3 4 5 6 7 8
36/M 60/M 58/M 69/F 28/M 42/F 34/F
Bilateral hippocampal high signal Left hippocampal high signal Normal Bilateral hippocampal high signal Bilateral hippocampal high signal Bilateral hippocampal high signal Bilateral hippocampal high signal
9 10
70/M 36/M
11 12
36/F 14/F
Seizures, amnesia and behavioural change Seizures, psychosis and amnesia Seizures, amnesia and depression Seizures, amnesia Confusion, amnesia and seizures Seizures, amnestic syndrome Seizures, psychosis and amnesia Orofacial dyskinesia, seizures, apnoeas, amnestic syndrome Seizures, amnestic syndrome Orofacial dyskinesia, amnestic syndrome, seizures Seizures, amnestic syndrome Orofacial dyskinesia, sleep wake reverals, seizures
4
3
CBZ, LEV None PHB, LEV None PHT LEV VPA PHB, OXC None
4 5 6 7 7 8 10
15 10 7 8 19 2 6
Bilateral hippocampal high signal Bilateral hippocampal high signal
VPA OXC, CLB
12 17
4 1
Bilateral hippocampal high signal Normal
TPM, CBZ, CLB VPA
9 4
19 4
Antibody
Cognitive impairment
VGKC
Mild
Negative Negative Negative VGKC Negative Negative NMDA
Severe Severe Mild None Severe Moderate None
VGKC NMDA
Mild None
Negative NMDA
None None
MRI, magnetic resonance imaging; PSQI, Pittsburgh sleep questionnaire inventory; ESS, Epworth sleepiness score. Medication: PHT, phenytoin; LEV, levitiracetam; VLP, sodium valproate; CBZ, carbamazepine; OXC, oxcarbazepine. Categorised impairments as mild if below 20th centile, moderate if below 5th centile, and severe if at or below 1st centile. Based on assessment either with BIRT Memory and Information Processing Battery (Coughlan, Oddy & Crawford, 2007) or Wechsler Memory Scale – III.
seizures over 6 days. Upon admission she was initially drowsy with frequent seizures. She was antibody negative but had typical MRI changes of bilateral hippocampal signal change. She was treated with anticonvulsants but had persistent epileptic and non-epileptic seizures and also a fixed amnestic syndrome as well as significant mood disturbance. These symptoms persisted during long-term follow up and were unchanged over serial cognitive assessments. She did not receive immunotherapy during the acute phase of the illness. At the point of assessment for sleep disturbance in 2010, she had fragmented unrefreshing night sleep with witnessed snoring, unpleasant vivid dreams but no definite dream enactment. ESS was elevated at 19 and PSQI was elevated at 12. She was maintained on topiramate, carbamazepine and clobazam. Overnight polysomnography showed fragmented night sleep with reduced sleep efficiency at 73.6%, no evidence of sleep disordered breathing or loss of REM atonia but restless legs which led to arousal from sleep and increased periodic limb movements (PLMI – 22). A trial of dopamine agonist was initiated and the patient remains under review. 4. Discussion To our knowledge this is the first study to systematically analyse the sleep disruption in long-term survivors of non-neoplastic limbic encephalitis. It is the first to describe polysomnography changes in those with NMDA-R limbic encephalitis. None of the patients described had any sleep complaints prior to their limbic encephalitis. Sleep disturbance during the acute phase of limbic encephalitis is well described although there are few polysomnography studies in the literature. Most has been written about the spectrum of sleep disturbance within voltage gated potassium channel
autoimmunity. This includes patients with neuromyotonia (Isaacs syndrome), Morvan syndrome and limbic encephalitis. Acute insomnia or hypersomnia has been described in 26% of patients with positive VGKC antibodies [17] but there was no polysomnography data in this series. REM sleep behaviour disorder (RBD) was described as occurring during the acute presentation of VGKC-Ab mediated limbic encephalitis by Vincent [3] and in more detail with polysomnography data by Iranzo [8]. It has been shown to resolve after immunotherapy [8,18]. The most recent study to review the sleep manifestations of VGKC-Ab patients looked at a series of 15 consecutive patients with positive antibodies and retrospectively assessed sleep data [9]. Three of these patients with limbic encephalitis had overnight polysomnography during the acute phase of the illness. Striking insomnia was described in two with no recordable sleep during overnight polysomnography, mild sleep disordered breathing, vivid dreams, loss of REM atonia and restless sleep was found in the third. Our study identified 12 patients under long-term follow up with a typical clinical presentation of limbic encephalitis who then completed the ESS and PSQI sleep screening questionnaires. The three patients with proven VGKC-Abs had normal ESS and only one had a significantly raised PSQI. None complained of persistent dream enactment behaviours or nightmares and all declined further investigation suggesting that this small group did not have persistent or troublesome sleep disturbance. There have been no polysomnography studies in patients surviving NMDA receptor mediated limbic encephalitis and this study identifies the novel finding of persistent, severe central sleep apnoea in one patient and severe periodic limb movements of sleep and restless legs in another. Dalmau first published a series of young women with paraneoplastic NMDA receptor antibody mediated limbic encephalitis
Table 2 Polysomnography data. Patient, case no.
SL
TST
SE
SWS
REM
AHI
PLMI
Comments
WB, 3 CD, 8 JB, 10
3 34.5 8.9
521 388 419
69 78 78
10.1 12.7 8.9
8.1 20.7 7.2
36.7 3.4 31.3
0 42.1 12.9
CM, 11
17.5
458
73.6
26.6
9.8
0.9
Limb movements during apnoeas Snoring Irregular breathing wake and asleep, central and obstructive apnoea Generally restless throughout night
21
SL, sleep latency; TST, total sleep time; SE, sleep efficiency calculated as percentage of total sleep time/time in bed; SWS, percentage of total sleep time in slow wave sleep; REM, percentage of time in REM sleep; AHI, apnoea hypopnoea index; PLMI, periodic limb movement index.
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with decreased level of consciousness as well as psychosis and hyperkinetic movement disorders. 4/12 were described as having “transient sleep dysfunction” while recovering from the encephalitis but no further details were given [19]. Subsequent case series [4,20] described insomnia in up to 34% with 1 in 6 long-term survivors having persistent insomnia. Poloni et al. [21] reported striking insomnia accompanying the acute prodrome in 4 children but no polysomnography data was reported. A single case of paraneoplastic anti-Ma2 limbic encephalitis used polysomnography to show abnormal sleep architecture and sudden onset REM periods consistent with a secondary narcolepsy [22]. One of our patients with proven NMDA-R limbic encephalitis had striking and persistent insomnia with persistent obstructive and central sleep apnoea and periodic limb movements of sleep. This occurred despite his NMDA-R antibodies becoming undetectable following immunotherapy. He had symptomatic benefit from CPAP therapy and dopamine agonists. He did not have a significantly elevated body mass index (BMI – 27) suggesting that the same central mechanisms that cause a number of brainstem related features can persist even when the pathogenic antibodies are no longer detectable. The precise mechanisms remain unclear. The second patient had significant restless legs with associated periodic limb movements with improved subjective sleep quality with dopaminergic therapy and objective improvement in depression and anxiety scores. In two antibody negative patients, ESS and PSQI were abnormal and subsequent polysomnography showed significant obstructive sleep apnoea in the first and restless legs and fragmented night sleep in the second patient. In all patients, there was a long interval between the symptoms of sleep disturbance and sleep evaluation (mean delay 40.3 months, range 3–96 months) suggesting that the initial symptoms of sleep disturbance were overlooked or possibly attributed to the other neurological deficits or sedative effects of medication used to treat for example seizures. No patients had overnight seizures seen on video telemetry. All patients with abnormal polysomnography had an abnormal PSQI but not ESS suggesting that this may be a more sensitive screening tool to look for the range of sleep disturbance seen in these conditions. There are several limitations to the study including a small sample size and a retrospective study design. Only some patients consented to further polysomnography so we cannot assess frequency of sleep disturbance in this population. The sleep disorders described are common and one cannot say that prevalence rates are increased beyond the background population. However the patients studied reported symptomatic sleep disturbance following their illness and in two cases this improved with therapy suggesting a potentially treatable cause of impaired daytime function. 5. Conclusions This small study highlights the occurrence of disturbed sleep as a long-term sequelae of immune mediated limbic encephalitis which may impact upon cognition, seizure frequency and quality of life. Further larger studies are warranted to assess the true frequency of sleep disorders in this population and most importantly to see if targeted interventions improve symptoms.
Acknowledgements We would like to thank Dr J Miller, Dr U Nath, Dr T. Williams and Dr M Jackson for contributing patients and the patients and families themselves. References [1] Vedeler CA, Storstein A. Autoimmune limbic encephalitis. Acta Neurologica Scandinavica, Supplementum 2009;(189):63–7. [2] Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P, Rosenfeld MR. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127(August (Pt 8)):1831–44. [3] Vincent A, Buckley C, Schott JM, Baker I, Dewar B-K, Detert N, Clover L, Parkinson A, Bien CG, Omer S, Lang B, Rossor MN, Palace J. Potassium channel antibodyassociated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004;127(March (Pt 3)):701–12. [4] Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurology 2008;7(December (12)):1091–8. [5] Bataller L, Kleopa KA, Wu GF, Rossi JE, Rosenfeld MR, Dalmau J. Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes. Journal of Neurology, Neurosurgery and Psychiatry 2007;78(April (4)):381–5. [6] Samarasekera SR, Vincent A, Welch JL, Jackson M, Nichols P, Griffiths TD. Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies. Journal of Neurology, Neurosurgery and Psychiatry 2007;78(April (4)):391–4. [7] Kawamura N, Kawajiri M, Ohyagi Y, Minohara M, Murai H, Kira J. A patient with paraneoplastic limbic encephalitis induced by breast cancer presenting with hypersomnia. Rinsho Shinkeigaku 2005;45(August (8)):575–8. [8] Iranzo A, Graus F, Clover L, Morera J, Bruna J, Vilar C, Martínez-Rodriguez JE, Vincent A, Santamaría J. Rapid eye movement sleep behavior disorder and potassium channel antibody-associated limbic encephalitis. Annals of Neurology 2006;59(January (1)):178–81. [9] Cornelius JR, Pittock SJ, McKeon A, Lennon VA, Aston PA, Josephs KA, TippmannPeikert M, Silber MH. Sleep manifestations of voltage-gated potassium channel complex autoimmunity. Archives of Neurology 2011;68(June (6)):733–8. [10] Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W, Hodges JR. A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 2000;55(December (11)):1613–20. [11] Wechsler DA. Weschler adult intelligence scale. 3rd ed. New York: Psychological Corporation; 1997. [12] Coughlan AK, Crawford JR, Oddy MJ. BIRT memory and information processing battery (BMIPB). London: Brain Injury Rehabilitation Trust; 2007. [13] Aita JA, Armitage SG. The use of certain psychological tests in the evaluation of brain injury. Journal of General Psychology 1947;37:25–44. [14] Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14(December (6)):540–5. [15] Buysse DJ, Reynolds CF3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Research 1989;28(May (2)):193–213. [16] Silber MH, Ancoli-Israel S, Bonnet MH, Chokroverty S, Grigg-Damberger MM, Hirshkowitz M, Kapen S, Keenan SA, Kryger MH, Penzel T, Pressman MR, Iber C. The visual scoring of sleep in adults. Journal of Clinical Sleep Medicine 2007;3(March (2)):121–31. [17] Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 2008;70(May (20)):1883–90. [18] Montiel P, Sellal F, Clerc C, Richard P, Bataillard M. Limbic encephalitis with severe sleep disorder associated with voltage-gated potassium channels (VGKCs) antibodies. Revue Neurologique 2008;164(February (2)):181–4. [19] Dalmau J, Tüzün E, Wu H-yan, Masjuan J, Rossi JE, Voloschin A, Baehring JM, Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR. Paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Annals of Neurology 2007;61(January (1)):25–36. [20] Irani SR, Vincent A. NMDA receptor antibody encephalitis. Current Neurology and Neuroscience Reports 2011;11(June (3)):298–304. [21] Poloni C, Korff CM, Ricotti V, King MD, Perez ER, Mayor-Dubois C, Haenggeli CA, Deonna T. Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti-N-methyl-d-aspartate receptor encephalitis. Developmental Medicine and Child Neurology 2010;52(May (5)):e78–82. [22] Landolfi JC, Nadkarni M. Paraneoplastic limbic encephalitis and possible narcolepsy in a patient with testicular cancer: case study. Neuro-oncology 2003;5(July (3)):214–6.
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Primary sleep disorders can cause long-term sleep disturbance in patients with autoimmune mediated limbic encephalitis Kirstie N. Anderson a,∗ , Thomas P. Kelly b , Timothy D. Griffiths b a b
Department of Neurology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom Institute of Neuroscience, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom
a r t i c l e
i n f o
Article history: Received 27 September 2011 Received in revised form 28 October 2012 Accepted 31 October 2012 Available online 21 November 2012 Keywords: Limbic encephalitis Sleep apnoea Restless legs
a b s t r a c t Objectives: Antibody mediated limbic encephalitis causes a sub acute encephalopathy with an amnestic syndrome, seizures and often an affective prodrome. Sleep disturbance including abnormal dream sleep and insomnia are described in a percentage of long-term survivors but there are very few detailed assessments of sleep disturbance in patients beyond the acute phase of illness. The objectives of this study were to understand the causes of sleep disturbance in the long-term survivors of antibody mediated limbic encephalitis. Patients and methods: We screened twelve patients under long-term follow up with sleep questionnaires and went on to perform detailed sleep studies (polysomnography) in those who reported sleep disturbance. Results: Two were found to have persistent, severe central and obstructive sleep apnoea and two others to have restless legs and periodic limb movements of sleep. Conclusions: This highlights the need to investigate sleep disturbance in this group of patients. Effective treatments may be available to improve quality of life and daytime function. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Autoimmune or paraneoplastic limbic encephalitis is increasingly recognised as a cause of sub acute encephalopathy with seizures and an amnestic syndrome [1]. The identification of antibodies to anti-Ma, anti-Hu, the voltage gated potassium channel (VGKC), the N-methyl-d-aspartate receptor (NMDA-R) and the AMPA receptor has highlighted the potential for immunotherapy for these disorders [2–4]. Additionally, a number of patients have a similar clinical presentation but do not have any of the currently described antibodies on clinical testing, although understanding of immunological bases is rapidly evolving [5,6]. A number of patients have prominent and early sleep-wake disturbance as a feature of the acute illness. Hypersomnia with fragmented night sleep has been described in patients with anti-Ma encephalitis [7]. NMDA-R encephalitis patients present with reduced levels of consciousness often with hypoventilation requiring mechanical ventilation [4]. VGKC limbic encephalitis is associated with REM sleep behaviour disorder that can reverse upon successful treatment [8,9].
∗ Corresponding author. Tel.: +44 0191 2823833; fax: +44 0191 2825027. E-mail address: [email protected] (K.N. Anderson). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2012.10.031
A percentage of long-term survivors have persistent sleep disturbance, usually insomnia (Dalmau J, personal communication). There have been very few reports of any patients having subjective or objective sleep assessments following recovery from the acute illness when under long-term follow up. We screened patients with confirmed, non-infective limbic encephalitis who underwent detailed sleep assessments following recovery from their acute illness. Two patients had persistent, severe sleep apnoea causing sleep fragmentation, one of whom was successfully treated with non-invasive ventilation. Two patients had periodic limb movements of sleep and associated restless legs syndrome causing insomnia and daytime sleepiness which again responded to treatment. None of our patients had REM sleep behaviour disorder after the acute phase of the illness.
2. Methods 2.1. Patients All patients presented to the Neurology service at the Newcastle upon Tyne acute hospitals trust between 2001 and 2010. They were in-patients during the acute phase of the illness then followed up within the cognitive neurology clinic. All patients had a subacute amnestic syndrome and seizures. All patients underwent MRI scanning and EEG. All underwent
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K.N. Anderson et al. / Clinical Neurology and Neurosurgery 115 (2013) 1079–1082
cerebrospinal fluid (CSF) examination, and serological testing to exclude herpes simplex virus infection. All patients underwent an extended autoantibody screen, including thyroid-peroxidase antibodies and anti-neuronal antibodies. Associated cancer was sought on the basis of screening investigations and clinical follow-up of between 18 and 48 months. All patients underwent CT scanning of the chest, abdomen and pelvis which was negative. All patients had screening memory assessment during the acute presentation using Addenbrooke’s Cognitive Examination [10]. All patients received subsequent detailed assessment including assessment of current intellectual function (Wechsler Adult Intelligence Scale, 3rd Ed.) [11] and memory function (BIRT Memory and Information Processing Battery; BMIPB) [12]. Executive function was assessed using the Trail Making and Controlled Verbal Fluency Tests [13]. The neuropsychological assessment took place at 2 months and at intervals of 6 and 12 months thereafter. Measurement of serum VGKC-Ab titres was carried out within 4 weeks of admission and defined as negative if <100 pM. Measurement of serum NMDA-R antibodies was determined by a cell-based assay (assays performed at John Radcliffe Hospital, Oxford, UK).
He had a significant residual memory deficit on repeated testing that prevented him from resuming work. His only long-term medication at the time of assessment for sleep disturbance was clomipramine. MRI initially showed left hippocampal signal change but this resolved upon rescanning at 6 months. He had obvious sleep disturbance that had started after his acute illness and persisted up to the time of assessment with disturbed dream sleep and evidence of dream enactment, he was restless in bed with loud snoring and witnessed apnoeas. ESS was 13 and PSQI was 6. Polysomnography confirmed severe obstructive sleep apnoea (AHI 36.7, ODI 43.3) but showed no evidence of REM sleep behaviour disorder although he had multiple arousals from REM sleep coinciding with apnoeas and causing vocalisations and occasional limb movements. Weight remained unchanged before and after the acute illness with a normal body mass index of 24.3. He trialled CPAP but was unable to tolerate it. 3.2. Patient CD (Case 8 in Table 1)
Patients completed the Epworth Sleepiness Score (ESS) [14] and the Pittsburgh Sleep Questionnaire Inventory (PSQI) [15]. Ten patients with abnormal values in either questionnaire (ESS >10 and/or PSQI >5) were invited to attend the Regional Sleep Service for clinical interview followed by polysomnography. Polysomnography was performed using a standard procedure, including video recording, a sleep electroencephalogram (leads C4-A1 and C3-A2), bilateral eye movements, submental EMG, and bilateral anterior tibialis EMG to record any leg movements during sleep. Respiratory movements were detected with chest and abdominal bands measuring inductance, airflow was detected with nasal cannulae measuring pressure, and oxygen saturation of arterial blood was measured. Airflow limitation and changes in respiratory movement were used to detect increased upper-airway resistance. All respiratory events and sleep stages were scored according to standard criteria [16].
Patient CD, female 34 years presented with a 2-week progressive history of confusion, dysarthria and orofacial dyskinesia. Progressive complex partial and then generalised seizures led to intubation and ventilation on ITU. Prolonged central apnoeas were noted during the ITU admission. NMDA-R antibodies were initially positive and she was treated with plasma exchange, intravenous steroids and then oral steroids for a 6-month period, repeat antibodies were negative. Seizures and dyskinesia ceased but she had residual memory deficits and persistent sleep disturbance with fragmented night sleep and daytime fatigue. She had severe Restless Legs Syndrome based on the International Restless Legs Syndrome Society definition. ESS was 7 and PSQI was 6. Subsequent polysomnography excluded sleep apnoea but showed periodic limb movements of sleep (PLMI – 42). Symptomatic benefit was obtained with a combination of gabapentin and pramipexole with decreased sleep fragmentation but also improvement in anxiety and depression ratings (Becks anxiety index – BAI and Becks depression inventory – BDI) with neuropsychology assessment before and after intervention for sleep disturbance. Before treatment BAI = 32 severe anxiety, BDI = 35 severe depression. After treatment BAI = 17 and BDI = 15.
3. Results
3.3. Patient JB (Case 10 in Table 1)
Twelve patients with limbic encephalitis completed sleep questionnaires. Their clinical details and sleep questionnaire results are summarised in Table 1. All patients had their sleep assessments >3 months after their acute presentation. ESS scores ranged between 1 and 19 (mean 7.2) with 3 patients reporting a score ≥10. The PSQI scores ranged between 4 and 17 (mean 7.5) with 8 patients having scores in the abnormal range of ≥5. Ten patients with abnormal sleep scores were approached for polysomnography studies and 4 underwent polysomnography. The others declined further investigation. The polysomnography results are summarised in Table 2. Patients with abnormal polysomnography are discussed in detail below.
Patient JB, a slim male 36 years with no prior sleep disturbance presented in March 2007 with subacute agitation, focal and generalised seizures and apnoeas leading to intubation and ventilation. Upon extubation he had prominent orofacial dyskinesia. NMDA receptor antibodies were initially positive but negative after immunotherapy. He was treated with plasma exchange and then high dose intravenous methylprednisolone followed by oral steroids for the next 6 months. Addenbrookes cognitive estimate was 93/100 in June 2007 but he had persistent anxiety, eating disorder and low mood. He complained of troublesome insomnia from discharge and his wife noted frequent prolonged apnoeas and periodic limb jerks but no snoring. His polysomnography showed frequent prolonged central apnoeas (apnoea hypopnoea index 31.7/h, 18/h central apnoea) and associated arousals from sleep. He was successfully treated with an autoset CS device used to treat predominantly central apnoeas (apnoea hypopnoea index on autoset CPAP 5.2/h). A low dose of pramipexole was subsequently commenced to treat restless legs. He had subjective benefit in daytime function.
2.2. Sleep assessment
3.1. Patient WB (Case 3 in Table 1) Patient WB, male 60 years presented with acute headache, behavioural change anterograde amnesia and complex partial and generalised seizures over a 6-week period. He was initially treated with anticonvulsants and subsequently with intravenous and then oral prednisolone but steroids were not commenced until 4 months after acute presentation. A diagnosis of antibody negative limbic encephalitis was found, and there was no evidence of malignancy.
3.4. Patient CM (Case 11 in Table 1) Patient CM 36-year-old female presented with subacute confusion, behaviour change and complex partial and generalised
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Table 1 Clinical data and investigations. Patient
Age/gender
Presenting features
MRI
Antiepileptic medication
PSQI
ESS
1
56/M
Bilateral hippocampal high signal
PHT
2 3 4 5 6 7 8
36/M 60/M 58/M 69/F 28/M 42/F 34/F
Bilateral hippocampal high signal Left hippocampal high signal Normal Bilateral hippocampal high signal Bilateral hippocampal high signal Bilateral hippocampal high signal Bilateral hippocampal high signal
9 10
70/M 36/M
11 12
36/F 14/F
Seizures, amnesia and behavioural change Seizures, psychosis and amnesia Seizures, amnesia and depression Seizures, amnesia Confusion, amnesia and seizures Seizures, amnestic syndrome Seizures, psychosis and amnesia Orofacial dyskinesia, seizures, apnoeas, amnestic syndrome Seizures, amnestic syndrome Orofacial dyskinesia, amnestic syndrome, seizures Seizures, amnestic syndrome Orofacial dyskinesia, sleep wake reverals, seizures
4
3
CBZ, LEV None PHB, LEV None PHT LEV VPA PHB, OXC None
4 5 6 7 7 8 10
15 10 7 8 19 2 6
Bilateral hippocampal high signal Bilateral hippocampal high signal
VPA OXC, CLB
12 17
4 1
Bilateral hippocampal high signal Normal
TPM, CBZ, CLB VPA
9 4
19 4
Antibody
Cognitive impairment
VGKC
Mild
Negative Negative Negative VGKC Negative Negative NMDA
Severe Severe Mild None Severe Moderate None
VGKC NMDA
Mild None
Negative NMDA
None None
MRI, magnetic resonance imaging; PSQI, Pittsburgh sleep questionnaire inventory; ESS, Epworth sleepiness score. Medication: PHT, phenytoin; LEV, levitiracetam; VLP, sodium valproate; CBZ, carbamazepine; OXC, oxcarbazepine. Categorised impairments as mild if below 20th centile, moderate if below 5th centile, and severe if at or below 1st centile. Based on assessment either with BIRT Memory and Information Processing Battery (Coughlan, Oddy & Crawford, 2007) or Wechsler Memory Scale – III.
seizures over 6 days. Upon admission she was initially drowsy with frequent seizures. She was antibody negative but had typical MRI changes of bilateral hippocampal signal change. She was treated with anticonvulsants but had persistent epileptic and non-epileptic seizures and also a fixed amnestic syndrome as well as significant mood disturbance. These symptoms persisted during long-term follow up and were unchanged over serial cognitive assessments. She did not receive immunotherapy during the acute phase of the illness. At the point of assessment for sleep disturbance in 2010, she had fragmented unrefreshing night sleep with witnessed snoring, unpleasant vivid dreams but no definite dream enactment. ESS was elevated at 19 and PSQI was elevated at 12. She was maintained on topiramate, carbamazepine and clobazam. Overnight polysomnography showed fragmented night sleep with reduced sleep efficiency at 73.6%, no evidence of sleep disordered breathing or loss of REM atonia but restless legs which led to arousal from sleep and increased periodic limb movements (PLMI – 22). A trial of dopamine agonist was initiated and the patient remains under review. 4. Discussion To our knowledge this is the first study to systematically analyse the sleep disruption in long-term survivors of non-neoplastic limbic encephalitis. It is the first to describe polysomnography changes in those with NMDA-R limbic encephalitis. None of the patients described had any sleep complaints prior to their limbic encephalitis. Sleep disturbance during the acute phase of limbic encephalitis is well described although there are few polysomnography studies in the literature. Most has been written about the spectrum of sleep disturbance within voltage gated potassium channel
autoimmunity. This includes patients with neuromyotonia (Isaacs syndrome), Morvan syndrome and limbic encephalitis. Acute insomnia or hypersomnia has been described in 26% of patients with positive VGKC antibodies [17] but there was no polysomnography data in this series. REM sleep behaviour disorder (RBD) was described as occurring during the acute presentation of VGKC-Ab mediated limbic encephalitis by Vincent [3] and in more detail with polysomnography data by Iranzo [8]. It has been shown to resolve after immunotherapy [8,18]. The most recent study to review the sleep manifestations of VGKC-Ab patients looked at a series of 15 consecutive patients with positive antibodies and retrospectively assessed sleep data [9]. Three of these patients with limbic encephalitis had overnight polysomnography during the acute phase of the illness. Striking insomnia was described in two with no recordable sleep during overnight polysomnography, mild sleep disordered breathing, vivid dreams, loss of REM atonia and restless sleep was found in the third. Our study identified 12 patients under long-term follow up with a typical clinical presentation of limbic encephalitis who then completed the ESS and PSQI sleep screening questionnaires. The three patients with proven VGKC-Abs had normal ESS and only one had a significantly raised PSQI. None complained of persistent dream enactment behaviours or nightmares and all declined further investigation suggesting that this small group did not have persistent or troublesome sleep disturbance. There have been no polysomnography studies in patients surviving NMDA receptor mediated limbic encephalitis and this study identifies the novel finding of persistent, severe central sleep apnoea in one patient and severe periodic limb movements of sleep and restless legs in another. Dalmau first published a series of young women with paraneoplastic NMDA receptor antibody mediated limbic encephalitis
Table 2 Polysomnography data. Patient, case no.
SL
TST
SE
SWS
REM
AHI
PLMI
Comments
WB, 3 CD, 8 JB, 10
3 34.5 8.9
521 388 419
69 78 78
10.1 12.7 8.9
8.1 20.7 7.2
36.7 3.4 31.3
0 42.1 12.9
CM, 11
17.5
458
73.6
26.6
9.8
0.9
Limb movements during apnoeas Snoring Irregular breathing wake and asleep, central and obstructive apnoea Generally restless throughout night
21
SL, sleep latency; TST, total sleep time; SE, sleep efficiency calculated as percentage of total sleep time/time in bed; SWS, percentage of total sleep time in slow wave sleep; REM, percentage of time in REM sleep; AHI, apnoea hypopnoea index; PLMI, periodic limb movement index.
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with decreased level of consciousness as well as psychosis and hyperkinetic movement disorders. 4/12 were described as having “transient sleep dysfunction” while recovering from the encephalitis but no further details were given [19]. Subsequent case series [4,20] described insomnia in up to 34% with 1 in 6 long-term survivors having persistent insomnia. Poloni et al. [21] reported striking insomnia accompanying the acute prodrome in 4 children but no polysomnography data was reported. A single case of paraneoplastic anti-Ma2 limbic encephalitis used polysomnography to show abnormal sleep architecture and sudden onset REM periods consistent with a secondary narcolepsy [22]. One of our patients with proven NMDA-R limbic encephalitis had striking and persistent insomnia with persistent obstructive and central sleep apnoea and periodic limb movements of sleep. This occurred despite his NMDA-R antibodies becoming undetectable following immunotherapy. He had symptomatic benefit from CPAP therapy and dopamine agonists. He did not have a significantly elevated body mass index (BMI – 27) suggesting that the same central mechanisms that cause a number of brainstem related features can persist even when the pathogenic antibodies are no longer detectable. The precise mechanisms remain unclear. The second patient had significant restless legs with associated periodic limb movements with improved subjective sleep quality with dopaminergic therapy and objective improvement in depression and anxiety scores. In two antibody negative patients, ESS and PSQI were abnormal and subsequent polysomnography showed significant obstructive sleep apnoea in the first and restless legs and fragmented night sleep in the second patient. In all patients, there was a long interval between the symptoms of sleep disturbance and sleep evaluation (mean delay 40.3 months, range 3–96 months) suggesting that the initial symptoms of sleep disturbance were overlooked or possibly attributed to the other neurological deficits or sedative effects of medication used to treat for example seizures. No patients had overnight seizures seen on video telemetry. All patients with abnormal polysomnography had an abnormal PSQI but not ESS suggesting that this may be a more sensitive screening tool to look for the range of sleep disturbance seen in these conditions. There are several limitations to the study including a small sample size and a retrospective study design. Only some patients consented to further polysomnography so we cannot assess frequency of sleep disturbance in this population. The sleep disorders described are common and one cannot say that prevalence rates are increased beyond the background population. However the patients studied reported symptomatic sleep disturbance following their illness and in two cases this improved with therapy suggesting a potentially treatable cause of impaired daytime function. 5. Conclusions This small study highlights the occurrence of disturbed sleep as a long-term sequelae of immune mediated limbic encephalitis which may impact upon cognition, seizure frequency and quality of life. Further larger studies are warranted to assess the true frequency of sleep disorders in this population and most importantly to see if targeted interventions improve symptoms.
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