Rapid Eye Movement Sleep Behavior Disorder in Paraneoplastic Cerebellar Degeneration: Improvement with Immunotherapy

Abstract

Study Objectives:

To report two female patients with paraneoplastic cerebellar degeneration (PCD) related to breast cancer that presented with rapid eye movement-sleep behavior disorder (RBD) and improved sleep symptoms with immunotherapy.

Methods:

The two patients were evaluated through clinical scale and polysomnography before and after therapy with intravenous immunoglobulin.

Results:

RBD was successfully treated with immunotherapy in both patients. Score on the RBD screening questionnaire dropped from 10 to 1 or 0, allied with the normalization of polysomnographic findings.

Conclusions:

A marked improvement in RBD after immunotherapy in PCD raises the hypothesis that secondary RBD may be an immune-mediated sleep disorder.

Citation:

Vale TC, do Prado LB, do Prado GF, Barsottini OG, Pedroso JL. Rapid eye movement sleep behavior disorder in paraneoplastic cerebellar degeneration: improvement with immunotherapy. SLEEP 2016;39(1):117–120.

Significance.

REM sleep behavior disorder (RBD) precedes or accompanies several neurodegenerative disorders. Recently, some authors have described RBD in immune mediated encephalopathies. This article highlights that RBD may be part of the clinical spectrum of paraneoplastic cerebellar degeneration. In addition, we demonstrated the benefit of immunotherapy for RBD in paraneoplastic cerebellar degeneration. This report gives new information about pathophysiological mechanisms of RBD related to immune mediated neurological conditions.

INTRODUCTION

Paraneoplastic cerebellar degeneration (PCD) is a rare disorder, more commonly associated with small cell lung cancer, gynecologic and breast cancer, and Hodgkin lymphoma.¹ Neurologic symptoms in PCD are characterized by subacute onset of global ataxia, diplopia, dysarthria, and dysphagia.² These symptoms usually precede the diagnosis of cancer in days, months, or up to 5 y.^1,2 The pathophysiological hallmarks for PCD are an extensive loss of Purkinje cells that might be associated with inflammatory infiltrates in the cerebellar cortex, deep cerebellar nuclei, and inferior olivary nuclei.³ Anti-Yo and Anti-Hu antibodies are the most common onconeural antibodies associated with PCD.⁴ They are directed against the cdr2 antigen expressed by Purkinje cells, resulting in destruction of neurons. The irreversible Purkinje cell loss causes predominantly cerebellar symptoms and significant disability.^1,4 Recently, several new antineuronal antibodies have been related with PCD, including anti-Ri, anti-CV2, Anti-Ma 2, anti-Gad65, and Anti-mGLuR1.⁵

Sleep disorders are rarely reported in paraneoplastic syndromes of the central nervous system (CNS). Rapid eye movement (REM)-sleep behavior disorder (RBD) is a parasomnia characterized by increased muscle activity associated with vigorous dream-enacting behaviors during REM sleep that is caused by brainstem and limbic system impairment.^6,7 There are only few sporadic reports of RBD associated with inflammatory diseases of the CNS, such as encephalitis.^8–14 RBD is most commonly related to neurodegenerative diseases, such as in alpha-synucleinopathies (Parkinson disease, dementia with Lewy bodies, and multiple system atrophy).^6,7

Herein we describe two patients with PCD presenting with marked RBD successfully treated with immunotherapy. We also discuss the possible mechanisms related to RBD in PCD.

PATIENT 1

In a 66-y-old woman, subacute ataxia developed 2 y ago. The patient became wheelchair bound in 3 mo. She also had diabetes and hypertension. Her husband also complained of restless sleep that began with motor symptoms. He reported that the patient had episodes of kicking, screaming, punching, and even jumping out of bed. Neurological examination disclosed severe axial and appendicular ataxia, and dysarthria. The patient scored 10 out of 13 points on the RBD screening questionnaire.¹⁴ Polysomnography (PSG) confirmed loss of atonia during REM sleep and ruled out other conditions such as epilepsy, obstructive sleep hypopnea/apnea, and periodic limb movement disorder. Brain magnetic resonance imaging (MRI) was normal. Routine laboratory workup, rheumatologic tests, and serologies were normal. Serum neoplastic bio-markers (cancer antigen 19.9, carcinoembryonic antigen, and alpha-fetoprotein) were negative. A cerebrospinal fluid (CSF) analysis was normal (1 cell/mm³ and 43 mg/dL of proteins). Other immune tests were negative: antiglutamic acid decarboxylase (anti-GAD), anti-endomysium, anti-gliadin, antithyroperoxidase, voltage-gated potassium channel (VGKC) and anti-N-methyl-d-aspartate receptor antibodies. A serum and CSF paraneoplastic antibodies panel including anti-Yo (Purkinje-cell antibody type 1-PCA1), PCA2, anti-P/Q-type voltage-gated calcium channel, anti-Tr, anti-Hu (antineuronal nuclear antibody-1[ANNA-1]), anti-Ri (ANNA-2), ANNA-3, anti-collapsin-response mediator protein 5 (CRMP or CV2), amphiphysin and anti-Ma were all negative. Fludeoxyglucose positron emission tomography/computed tomography (¹⁸FDG-PET/CT) performed in October 2013 revealed a right breast cancer. The patient underwent cancer treatment with surgery, radiotherapy, and chemotherapy. Intravenous immunoglobulin (IV Ig) was initially done in November 2013 (5 d of IV Ig 0.4 g/kg). The patient had immediate and complete improvement in RBD (score on the RBD screening questionnaire¹⁵ dropped from 10 to 1). She had partial improvement of ataxia after three additional cycles of IV Ig. Scale for the Assessment and Rating of Ataxia (SARA)¹⁶ score was initially 24 and dropped to 16.

PATIENT 2

A 43-y-old woman presented with a rapid onset of ataxia and dysarthria that progressed in an 11-mo period. For the previous 3 y, she complained of vivid dreams and dream enactment. Her sister observed restless sleep, kicking, and screaming. She scored 10 out of 13 on the RBD screening questionnaire¹⁴ and PSG disclosed loss of atonia during REM sleep (Figure 1A). Epilepsy, obstructive sleep hypopnea/ apnea, and periodic limb movement disorder were ruled out. Brain MRI showed mild cerebellar atrophy. CSF was normal (2 cells/mm³ and 28 mg/dL of proteins). Routine laboratory workup, rheumatic tests, serologies, and serum neoplastic biomarkers were negative. She underwent cervical, thoracic, abdominal and pelvic computed tomography scans as well as mammography. Computed tomography revealed bilateral breast nodules and investigation confirmed invasive ductal carcinoma. Adjunctive chemotherapy and mastectomy were performed and axillar lymph node metastasis was noted, prompting a radiotherapy scheme. ¹⁸FDG-PET/CT revealed no other metastatic foci. A serum and CSF paraneoplastic antibodies panel including anti-Yo, PCA2, anti-P/Q-type voltage-gated calcium channel, anti-Tr, anti-Hu, anti-Ri, ANNA-3, CRMP, amphiphysin, and anti-Ma yielded negative results. Four months after cancer therapy, the patient received five cycles of IV Ig and RBD symptoms improved immediately after the first cycle (RBD screening questionnaire score¹⁵ dropped from 10 to 0). PSG in follow-up was normal (Figure 1B). Ataxia did not improve.

Figure 1.

Polysomnographic recording of Patient 2 with rapid eye movement (REM) sleep behavior disorder and paraneoplastic cerebellar degeneration. (A) First polysomnographic recording, before immunoglobulin, disclosing paradoxical high amplitude of submental muscle, characterizing REM sleep without atonia phenomenon for this interval (red arrow). (B) Second polysomnographic recording, after immunoglobulin, discloses no abnormalities in the amplitude of submental muscle and highlights atonia duration REM sleep (red arrow).

DISCUSSION

RBD precedes or accompanies several neurodegenerative disorders. In alpha-synucleinopathies, including dementia with Lewy bodies, Parkinson disease, and multiple system atrophy, the prevalence of RBD varies from 19% to almost 77% in different reports.^6,7 In tauopathies, including Alzheimer disease, corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia, the prevalence is rare, ranging from zero to 27%.^6,7 Recently, Sabater and colleagues⁸ reported eight patients with a novel parasomnia with sleep breathing dysfunction associated with IgG4 antibodies to IgLON5, a neuronal surface cell adhesion molecule, and extensive deposits of hyperphosphorylated tau in the tegmentum and hypothalamus. RBD has, however, also been described in amyotrophic lateral sclerosis, limbic encephalitis, Guillain-Barré syndrome (GBS), Tourette syndrome, autism, epilepsy, and posttraumatic stress disorder.^6,7 RBD can also be induced by drugs such as antidepressants and alcohol withdrawal syndrome.^6,7

As for pathophysiological mechanisms, it is accepted that RBD may arise from a dysfunction in the REM sleep regulatory centers in the brainstem. An alteration of this circuitry probably allows dream-related motor programs from the cortex to reach the effector muscles during REM sleep, explaining the dream enactment behavior seen in RBD.⁷ One can postulate that a primary dysfunction of centers projecting to the brainstem, such as the cerebellum and limbic system, could be the explanation of having RBD in the context of a cerebellar disorder or limbic encephalitis. In fact, descriptions of the latter condition associated with RBD were already reported without clinical or neuroradiological evidence of brainstem involvement,^9–14 thus raising the hypothesis of an involvement of the limbic system in the genesis of RBD. The limbic system is strongly activated in physiological REM sleep, probably mediating the emotional content of dreams.^7,17 With regard to the cerebellar involvement, Pedroso et al.¹⁸ have shown almost 50% of their series of patients with spinocerebellar ataxia type 3 (SCA3) have RBD. The underlying involvement of midbrain cholinergic and pontine noradrenergic systems seen in SCA3 patients could in part explain these high rates of RBD.¹⁸

In this article, two cases of symptomatic RBD related to paraneoplastic syndrome of the CNS are described. A seronegative PCD was diagnosed after identification of an underlying cancer and demonstration of absence of other etiology. Of note, both cases had a complete resolution of sleep symptoms after using short-term IV Ig, revealing an autoimmune-mediated mechanism to explain RBD. Iranzo et al.¹³ reported five patients with nonparaneoplastic limbic encephalitis associated with antibodies to VGKC in whom RBD developed. Three of these patients had resolution of symptoms with immunosuppression in parallel with remission of the limbic syndrome. This study is another example that RBD might have an immune-mediated pathogenesis.¹³ RBD has also been reported in acute inflammatory demyelinating polyneuropathy (GBS) together with other REM sleep abnormalities. Interestingly, a spontaneous complete remission over time, paralleling neurological functional recovery, was observed in some cases and confirmed by PSG.^7,19 On the basis of these observations, Cochen et al.¹⁹ hypothesized that GBS autoantibodies could also target certain structures of the CNS, in particular the lateral hypothamalus, where orexinergic/hypocretinergic neurons are located. In the context of PCD, the hypothetical pathway through which auto-antibodies interact with the brainstem REM-on and REM-off areas and circuits has yet to be clearly outlined.

In conclusion, the case reports highlight that RBD may be part of the clinical spectrum of PCD. We are unaware whether primary cerebellar involvement or immune-mediated impairment in brainstem structures was the mechanism responsible for RBD in PCD. Increasingly, immunological disorders affecting the CNS have been described, and herein we proved the benefit of immunotherapy for a presumed immune-mediated sleep disorder.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest. Patients have consented with the publication of this manuscript.