Rivastigmine for parkinsonian symptoms in dementia with Lewy bodies: a paradigm shift

ABSTRACT

Introduction

Parkinsonian symptoms are one of the core features of Dementia with Lewy bodies (DLB), which has a prevalence of more than 80%. Management of DLB poses unique challenges as the treatment of one condition leads to the worsening of another. Rivastigmine’s efficacy and tolerability for cognitive and neuropsychiatric symptoms are well-studied. However, its effect on parkinsonian symptoms of DLB is inconclusive.

Clinical case series

In this case series, we elucidated five clinically diagnosed subjects of DLB with varying severity of parkinsonian motor symptoms. Beyond the cardinal signs of parkinsonism (tremor, rigidity, bradykinesia); rigidity, hypomimia, and gait disturbances were common in all the subjects. All five subjects on Rivastigmine dosage of 3–4.5 mg/day showed a greater than 50% reduction in the Unified Parkinson’s Disease rating scale part III without any untoward side effects. Hypomimia, stiffness, gait, and postural abnormalities were the motor signs that were substantially improved while resting tremors showed the least improvement.

Discussion

The study findings focus on the need to reflect upon the non-cholinergic deficiency hypothesis in developing motor symptoms in DLB. The distinct pathophysiology of DLB and the complex interactions of cholinergic and dopaminergic neurons in the striatum can explain the improvement in parkinsonian symptoms with Rivastigmine.

Conclusion

This case series highlights the positive effect of low-dose Rivastigmine on parkinsonian motor symptoms of DLB prompting the need for further multicentric trials.

Plain Language Summary

Parkinsonian symptoms comprising stiffness in body, difficulty in walking and shakiness in limbs on rest are one of the core features of Dementia with Lewy bodies (DLB) and management of these symptoms poses unique challenges as the treatment of one feature of the DLB leads to the worsening of another. Effectiveness and safety of Rivastigmine, an antidementia medication for difficulty in learning and memory functions and behavioral symptoms of DLB are well-studied. However, the effect of Rivastigmine on parkinsonian symptoms of DLB is inconclusive. Here, we are reporting the effect of Rivastigmine on five clinically diagnosed DLB subjects with varying severity of parkinsonian symptoms related to movement. The stiffness, difficulty in walking and reduced facial expressions were common in all the subjects. All five subjects on Rivastigmine dosage of 3–4.5 mg/day showed a greater than 50% reduction in symptoms without any untoward side effects. Reduced facial expressions, stiffness, difficulty in walking and inability to maintain balance substantially improved, while shakiness in hands showed the least improvement. This case series shows the positive effect of low-dose Rivastigmine on parkinsonian symptoms in DLB prompting the need for further exploration.

1. Introduction

Dementia with Lewy bodies (DLB) is the third most common cause of dementia, followed by Alzheimer’s Disease and Vascular Dementia with a population prevalence of 0.3 to 24.4% of all dementia cases [1,2]. Clinically, DLB presents with the following core features: fluctuations in cognition, impairment in attention, rapid-eye movement sleep behavior disorder (REMBD), well-formed visual hallucinations, and parkinsonism. However, the presence of motor symptoms of parkinsonism in DLB varies greatly, with a prevalence ranging from 34 to 60% based on the inclusivity in the definition of parkinsonism [3]. Additionally, DLB’s motor symptoms of parkinsonism differ from those of Idiopathic Parkinson’s Disease (PD), with bradykinesia and gait disturbance being more common, and its symmetrical involvement as opposed to PD’s classical asymmetric tremor predominance [4]. DLB differs from Parkinson’s disease dementia by the chronology of appearance of motor and cognitive symptoms.

The management of DLB is complex and requires multidisciplinary team approach. Acetylcholinesterase inhibitors (AChEIs) and memantine are efficacious for cognitive and neuropsychiatric symptoms in DLB [5]. Interestingly, Levodopa is less effective in treating motor symptoms in DLB unlike PD, and often worsens neuropsychiatric problems [6]. Thereby, non-dopaminergic hypothesis of parkinsonism in DLB needs further exploration for effective management. Despite, the significant challenges posed to both patients with DLB and caregivers by untreated motor symptoms, research is scarce and it requires diligent therapeutic attention. There is conflicting evidence on the effect of cholinesterase inhibitors on motor symptoms in DLB [7,8]. This case series investigates five cases with DLB on AChEI, Rivastigmine, and its impact on motor symptoms.

2. Case series

2.1. Case 1

Mr A, a 68-year-old right-handed male graduate, presented with an insidious onset 4-year history of acting out in dreams with increasing frequency like screaming, kicking, and boxing in the air around an hour after he sleeps. He would often claim that his colleagues had visited him and he would speak with some imaginary people and offer them food. Mr A also developed forgetfulness for the past 2 years as he would misplace his belongings and would forget if he had his meals. He would make mistakes in handling money and had difficulty finding the washroom at his home. Concurrently, Mr A had changes in his walking pattern as he would walk slowly and had a change in his voice.

On examination, Mr A had hypophonia and hypomimia with a reduced blink rate. Moreover, he had bradykinesia, and mild resting tremors, with a festinate gait and freezing. Mental status examination revealed restricted affect, well-formed visual hallucinations, poor judgment, and insight. The baseline scales were applied (Table 1) and cognitive examination including immediate and recent memory, attention, visuospatial, and executive functions were impaired. Routine laboratory investigations were within normal range and his Magnetic Resonance Imaging (MRI) revealed diffuse cerebral atrophy. He was provisionally diagnosed as a case of DLB according to the Consortium on Dementia with Lewy Bodies’ revised criteria [11].

Table 1.

Sociodemographic and baseline clinical characteristics of the cases with DLB.

Cases	Age	Sex	Education	Occupation	HMSE	NPI 12	DLBCRS	UPDRS PART-3
CASE 1	68	M	Graduate	Teacher	15	44	6	14
CASE 2	75	F	Graduate	Doctor	20	60	8	35
CASE 3	69	M	High School	Shopkeeper	10	68	10	53
CASE 4	77	M	Graduate	Banker	18	58	7	29
CASE 5	68	F	Illiterate	Housewife	11	62	10	36

Abbreviations: DLB = Dementia with Lewy Bodies; M = Male; F = Female; HMSE = Hindi Mental Status Examination, NPI 12 = Neuropsychiatric Inventory [9] 12; DLBCRS = Dementia with Lewy Bodies Composite Risk Score [10]; UPDRS = Unified Parkinson’s Disease Rating Scale.

Mr A was treatment-naïve and he was commenced on Rivastigmine 3 mg in divided doses, which was increased to 4.5 mg in a week, and a Melatonin tablet of 5 mg for REMBD. Alongside, psychoeducation to the family members, behavioral intervention, and reorientation were done. Upon assessment, after 2 weeks, there was significant improvement in his symptoms which was maintained for the following 1 and a half years with only 2 points decrease in his Hindi Mental State Examination (HMSE) score (Table 2) [12].

Table 2.

Change in mean UPDRS score of the subjects with DLB on Rivastigmine.

Updrs part 3	Baseline (Mean)	Last visit (Mean)	Percentage change from baseline to last visit
Speech	1.8	0.8	56
Facial expression	3.2	0.6	81.3
Resting tremor	2.2	1.6	27.3
Action tremor	2.6	0.8	69.3
Rigidity	2.6	0.8	69.3
Finger tapping	2.2	1	54.6
Hand movement	2	0.8	60
Rapid Alternating movement	2.2	1	54.6
Leg agility	2.2	1	54.6
Arising from chair	2.8	1	64.3
Posture	2	0.4	80
Gait	3	0.8	73.4
Postural instability	1.8	0.8	55.6
Slow movement	2.8	1.2	57.2
Total score	33.4	14.8	55.7

Abbreviations: UPDRS = Unified Parkinson’s Disease Rating Scale; DLB = Dementia with Lewy Bodies.

2.2. Case 2

Mrs B a 75-year-old female graduate, presented with forgetfulness and seeing persons not seen by others for the last 3 years. She was hypertensive but well-controlled on medication. The illness started with forgetting to close the door, switching off the gas stove, and leaving the water tap running, which was insidious in onset and gradually progressive for the last 3 years. At times, she would blame family members for stealing her items. Mrs B was noticed to forget her way back from the morning walk and it gradually increased in frequency. Within 6 months of the onset of forgetfulness, the husband noticed tremulousness in her hands and a lack of expressions on her face; there was slowness and stiffness in her body movements, and her handwriting became ineligible, hampering her activities. Additionally, she would fall repeatedly and had complaints of dizziness and constipation. Further, Mrs B started speaking to herself and would often go upstairs to serve tea on empty chairs, claiming that her relatives were sitting on the chairs.

Mrs B had hypophonia, hypomimia and micrographia. On further assessment, she had bradykinesia, tremors (resting and postural) with cogwheel rigidity, and decreased arm swing. She also had anxious preoccupation, delusion of theft, and visual, and auditory hallucinations with insight grade 1. The baseline scales were applied (Table 1) and cognitive functions including attention, recent memory, executive function, and visuospatial functions were impaired. Mrs B’s laboratory tests and ECG revealed no abnormality, but her MRI Brain revealed age-related cortical atrophy. She was diagnosed clinically as provisional DLB based on the Consortium on Dementia with Lewy Bodies revised criteria [11].

Mrs B was commenced on Rivastigmine with a dosage of 3 mg/day in divided doses and Melatonin 5 mg at night. Her voice, facial expressions, gait, rigidity, and dizziness improved significantly within a week. However, mild resting tremors and micrographia were still persistent. The Unified Parkinson’s Disease Rating Scale score (UPDRS) part III reduced significantly after 2 weeks (Table 2) and she is maintaining well on follow-up of 2 years on the same medication [13].

2.3. Case 3

Mr C, a 69-year-old married Muslim male, presented with complaints of gradually progressive episodes of abnormal limb movements at night for the last 5 years. His face appeared dull and he would remain sleepy throughout the day for the last 4 years. Mr C gradually developed slowness in his walking and a change in gait; there was a history of repeated falls and tremulousness in both hands. He also had difficulty recognizing his relatives and difficulty in finding his way to the washrooms at home for 4 years. He had a muffled voice and he would hold saliva in his mouth.

Mr C had dysarthria, hypomimia, and hypersalivation. Postural instability, freezing, and a short-stepped gait with forward bending were present while walking. He had bradykinesia, lead pipe rigidity in all four limbs, and tremors in the upper limbs (postural and intention). On neurocognitive evaluation, orientation, attention, executive function, visuospatial, and memory (immediate & recent) were impaired, and scales were applied at baseline (Table 1). MRI of the brain revealed diffuse cerebral atrophy with ventricular dilatation. Mr C was provisionally diagnosed with a case of DLB based on the Consortium on Dementia with Lewy Bodies revised criteria [11].

On admission, he commenced on oral Melatonin 10 mg at bedtime for REMBD, Reorientation strategies were applied and family members were psycho-educated regarding the illness. Rivastigmine 3 mg was started in divided doses which was gradually increased to 4.5 mg. There was improvement in his facial expressions and drooling of saliva and speech. He started walking upright and his steps got wider without any further episode of fall. There was the persistence of REMBD which improved in due course after commencement of Clonazepam 0.25 mg at night. Significant improvement in his symptoms was observed on objective assessment after 2 weeks (Table 2) and was stable throughout a follow-up of 6 months.

2.4. Case 4

Mr D a 77-year-old graduate, presented with forgetfulness and seeing images not seen by others for 8 months. Symptoms had an insidious onset characterized by misplacing belongings, forgetting passwords, and difficulty handling finances and using appliances. There were episodes during the day when he would talk alone in his room, and, on inquiry, he would tell his relatives were sitting with him and often ordered his son to serve them food; gradually it happened even during the nighttime disrupting his sleep.

Mr D’s speech was slurred, output was decreased, and masking of his face was present. Examination revealed bilateral rigidity in upper limbs (Left > Right), postural tremor, and bradykinesia in all four limbs. Well-formed visual hallucinations were present, and recent memory, executive function, and visuospatial functions were impaired and his baseline rating scale scores were documented (Table 1). Routine laboratory investigation and neuroimaging findings were noncontributory. He was diagnosed with DLB based on the Consortium on Dementia with Lewy Bodies revised criteria [11].

Mr D was commenced on Rivastigmine 3 mg/day in divided doses along with reorientation strategies, psychoeducation to the family and the behavioral interventions. Surprisingly, improvement in visual hallucinations, sleep, and attention were noticed within a week of treatment. His motor symptoms improved, as evidenced by a decrease in the UPDRS part III scores, and is maintained on the same for the last 2.5 years follow-up (Table 2).

2.5. Case 5

Mrs E a 68-year-old, right-handed female, illiterate, presented with forgetfulness for 3 years, difficulty finding ways for 2.5 years, and seeing objects not seen by others for 2 years. Symptoms started insidiously with forgetfulness as she would often find it difficult to mix proper ingredients while cooking, forget to switch off the gas stove; misplacing kitchen items. In due course, she would often have difficulty finding the washroom and would urinate in corners of her room. There were times when she was seen sitting alone staring at something and would try to feed or cover the child pointing to an empty bed. She would also offer food on the dining table to some imaginary relatives and speak with them. Mrs E also had episodes of screaming incoherently in the later part of her sleep during the night which would often disturb her husband’s sleep.

Mrs E’s psychomotor activity was increased, hypomimia, decreased blink rate, and short-stepped gait were present. On examination, bradykinesia and lead pipe rigidity were present in all four limbs, and bilateral mild hand tremors (postural and resting) were present. On mental status examination, affect was restricted, visual and auditory hallucinations were present, and judgment and reasoning were impaired. The neuropsychological evaluation revealed impairment in attention, naming, recent memory, orientation, executive function, and visuospatial function, and rating scales were applied (Table 1). The laboratory investigations were normal, and neuroimaging showed generalized age-related atrophy. She was provisionally diagnosed as a case of possible DLB based on the Consortium on Dementia with Lewy Bodies revised criteria [11].

The management included non-pharmacological intervention for the behavioral symptoms. Further, she was commenced on Melatonin 10 mg for sleep and Rivastigmine 3 mg per day in divided doses, which improved her visual hallucinations, motor symptoms, and cognition (Table 2). For the persistent auditory hallucination, Risperidone 0.5 mg per day in divided doses was given. She has been on regular follow-ups for the last 1 year, the dose of Rivastigmine was further increased to 4.5 mg and other medications were continued in the same dose.

3. Discussion

Rivastigmine was found to alleviate motor symptoms in addition to cognitive and neuropsychiatric symptoms in five clinically diagnosed cases of possible DLB in this study. The efficacy and tolerability of Rivastigmine in treating the cognitive and neuropsychiatric symptoms in DLB have a relatively wide base of evidence in the literature [7,14–16]. Despite, the presence of parkinsonian motor features in more than 85% of DLB cases during the disease course, only a few studies addressed the management of the same in DLB [5,11,17]. The available literature on the effect of Levodopa on parkinsonian symptoms of DLB reveals an improvement in 32 to 50% of cases [18]. Nevertheless, one in three patients with DLB on levodopa experience undesirable side effects, most frequently psychotic symptoms, which restricts its use [19]. Additionally, there are recent studies on the effectiveness of adjunct Zonisamide with Levodopa in parkinsonian symptoms of DLB with no effect on neuropsychiatric and cognitive symptoms but the evidence is limited [20–22].

The effect of AChEI on parkinsonian motor symptoms in DLB has discrepant results [7,8,23–25]. Our study reports more than 50% reduction in UPDRS part III scores of the patients with DLB indicating improvement in parkinsonian motor symptoms on Rivastigmine treatment (Table 2). Rivastigmine in DLB positively impacts parkinsonian symptoms in the long term except for reversible transient worsening of resting tremor in two studies [7,8]. However, the subjects included in the studies had lower scores on UPDRS at the baseline and the effect of Levodopa which was used concurrently cannot be excluded. It is noteworthy that the cases in our study represent variable severity of parkinsonism and are free from the effect of antiparkinsonian drugs. In contrast to our study findings, there are reports of worsening of the parkinsonian symptoms in DLB on donepezil [23,24]. Rivastigmine has dual cholinesterase inhibitor property which is different from Donepezil explaining the variation of motor outcome in patients with DLB [26,27]. Nonetheless, in a few studies, the deterioration of parkinsonian symptoms in patients with DLB was noted in association with a higher dose of Rivastigmine which was reversed on dose adjustment [8]. Similarly, the dose of rivastigmine in our study was 3 mg per day in divided doses except in two case. This highlights the possible dose-dependent effect of rivastigmine on the parkinsonian motor symptoms of DLB which needs further exploration.

The above-described cases present with a wide range of subtle motor symptoms beyond the three cardinal features of parkinsonism. Notably, in our study, Rivastigmine had a positive effect on bradykinesia, rigidity, hypomimia, freezing of gait, postural instability, and speech disturbances. Moreover, Rivastigmine is found to have a beneficial effect on gait, balance, freezing, fine motor movement, and postural instability, in patients with other neurodegenerative dementias [27–29].

The predominant pathophysiology of DLB is extensive deficiency of acetylcholine neurotransmitters in brain cortex with preservation of postsynaptic receptors. Additionally, patients with DLB have dopaminergic deficits in the striatum [30]. However, it differs from PDD by the associated reduction in D2 receptors which explains its relative non-responsiveness to Levodopa for parkinsonian symptoms and severe neuroleptic sensitivity [31]. The cholinergic pathway from the basal forebrain has a regulatory influence on the striatal dopaminergic activity via nicotinic cholinergic receptors [32]. The disruption of cholinergic output from the cortex to the striatum leads to the development of motor disturbances as evidenced in experimental studies [33]. Owing to the reduced binding capacity of the striatal nicotinic and muscarinic receptors in DLB, the increased cholinergic activity following the administration of Rivastigmine is hypothesized to increase the striatal dopaminergic activity maintaining the fine balance between the two [34]. This sheds light on the complex striatal cholinergic-dopaminergic interaction in DLB rather than the oversimplistic antagonistic theory in PD for the development of motor symptoms. Rivastigmine also improves cognitive functions by increasing cortical cholinergic activity which also has an impact on motor functions [27]. However, these observations indicate the need for further research and clinical observations to have confirmatory evidence.

4. Conclusion

With the gap in evidence for treating motor symptoms in DLB without any untoward side effects, there is a clear need for newer treatment options. This case series highlights the clinical effect of Rivastigmine in low doses on parkinsonian motor symptoms of DLB. Future multicentric blinded clinical trials with larger sample sizes are warranted for generalizing the findings and developing a standardized management approach for patients with DLB.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Article highlights

• Parkinsonian motor symptoms are prevalent in more than 80% cases of DLB (Dementia with Lewy Bodies).

• The motor symptoms in DLB are hypothesized to be due to complex cholinergic-dopaminergic interaction in striatum.

• Rivastigmine reduced more than 50% of motor symptoms as observed in the five subjects with DLB.

• The dose of rivastigmine showing improvement in motor symptoms in the reported subjects ranged from 3 mg to 4.5 mg.

• No adverse effects were reported in the study subjects with the low dose of rivastigmine.

Disclosure statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.