Neurol Ther (2018) 7:13–22 https://doi.org/10.1007/s40120-017-0090-8 COMMENTARY Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives Elisabet Londos Received: November 1, 2017 / Published online: December 19, 2017 The Author(s) 2017. This article is an open access publication Keywords: Dementia with Lewy bodies; ABSTRACT Experiences of a sufferer; Lewy body disease; Treatment This article describes the practical considera- tions in the clinical medical treatment in dementia with Lewy body (DLB) patients. It is illustrated with the voice of a DLB sufferer and INTRODUCTION his wife. According to our experience, emanat- ing from a 15 year collaboration between a In a meta-analysis of pharmacological treat- doctor and a nurse at a memory clinic, there are ments of Lewy body dementia, Stinton et al. several possible therapeutical entrances. How- concluded that ‘‘high-level evidence related to ever, the order in which the medication is pharmacological strategies for managing Lewy introduced is of great importance to avoid body dementia is rare’’, and that the patients’ and aggravation of other DLB symptoms. We start caregivers’ opinions about pharmacological the treatment with cholinesterase inhibitor and strategies have not been investigated (2015) . memantine, and; thereafter, we treat the most Our dementia with Lewy bodies (DLB) disturbing symptom. Thereafter, we consider if patients at the memory clinic, Skane University orthostatic hypotension is present and treat it. Hospital, Sweden all participate in a specially In the treatment of depression and anxiety it is designed follow-up programme involving yearly beneﬁcial to use agents affecting both nora- visits with a nurse and physician that include drenalin and serotonin. Dysphagia may be cognitive testing, blood pressure measurements, lethal but can be improved with carbohydrate electrocardiogram (ECG) and Neuropsychiatric drinks. These and other aspects are commented Inventory (NPI). Some of these patients are also upon from our experience and are also reﬂected included in programs with a wider range of in relation to studies evaluating the existing investigations involving the cerebro-spinal ﬂuid level of evidence. (CSF), positron emission tomography (PET) and magnetic resonance imaging (MRI). In between Enhanced content To view enhanced content for this these visits we are available for telephone article go to.http://www.medengine.com/Redeem/ consultations. BBFCF06003B9E24C. Here, we want to present experiences of our treatment strategies in DLB developed during E. Londos (&) Memory Research Unit, Inst of Clinical Sciences 15 years of cooperation between the same doc- Malmo¨, Lund University, Lund, Sweden tor and nurse, and also illustrate it with the e-mail: email@example.com 14 Neurol Ther (2018) 7:13–22 voice a patient and his wife. Informed consent grandchildren, he is back on the board of his was obtained from all patient(s) for being company. But we know that we have to prepare included in the study. and ‘pay’ by resting before and after undertak- ing more unusual activities. When the tiredness hits him, I no longer get scared. I let him rest WRITTEN DESCRIPTION and have conﬁdence in the experience that he OF THE ILLNESS FROM THE WIFE will get better again, and he does’’. OF THE PATIENT (TRANSLATED) THE PATIENT’S EXPERIENCE ‘‘The ﬁrst time I noticed that my husband was OF THE TREATMENT, BASED ill, he was 79 years old. He had come home late from a business meeting and damaged his car ON AN INTERVIEW driving it right into the wall of the garage. He was very tired and went straight to bed. The day ‘‘Following treatment, I feel that the joy of liv- after, he told me that he had been obliged to ing has returned. I have become better. I have stop on the highway to sleep in the car in order gotten my life back! I have always asked much to be able to drive all the way home. I was of myself but with this disease I have had to worried and made an appointment with a doc- learn to listen to my body. I still think it is tor for him. The conclusion after the consulta- annoying, however, when I forget names and tion was that he was stressed and ‘burned out’. the TV programs I have watched. Nowadays I He became worse and worse. On several occa- can travel alone by airplane and participate in sions I had to call 911 because I suspected he the board meetings of my company, but I have suffered a stroke! On his third time at the to prepare myself by sleeping almost 2 days and emergency unit, we met a doctor who took the nights before the meeting and at lunch-time symptoms seriously and conducted an investi- during the meeting. I have become generally gation. After a week at the hospital my husband stronger and walk 30–40 min daily. The incen- was discharged with the diagnosis ‘Dementia tive for me to cope with my disease is to be able NOS’. He could not walk without a walking to continue to lead my company. I would never frame, he fell when he got up at night and could have been able to manage all this without my not sit on the toilet without support. He was so wife, who takes such good care of me. I used to tired and just wanted to lie in his bed. It did not have a lot of unpleasant dreams, nightmares, get better. I thought it was hopeless’’. but they have disappeared. As have the ﬁgures I The wife also told us that after several used to see during daytime. I never see them months, the solution seemed to be a nursing nowadays. The most disturbing symptom for home. ‘‘But then we managed to get an me is the immense tiredness which makes me appointment at the Memory Clinic with a feel as if my brain is not catching up. But doctor and a nurse. Step by step, the medication compared to where I could have been—I have was changed and new drugs were added. A low gotten my life back!’’ blood pressure in the standing position was also found. In parallel with the medication changes COMMENTS ON THE EXPERIENCES and dose escalations, my husband was instruc- OF THE WIFE AND PATIENT ted to walk outside every day, initially for 10 min. He was also instructed to rest in the The patient expresses gratitude towards his wife afternoons and before undertaking strenuous activities. They explained that the disease (DLB) and the work she puts into their lives; this reﬂects good insight of the DLB patient. We ﬂuctuates, and that a decline does not neces- sarily mean a permanent deterioration, but that have often speculated about the great engage- ment of the wives of our DLB patients (who are with rest he will return to his starting position. Today, three years later, I must say he is well. in a great majority men) and have come to a We can travel with our children and plausible conclusion. The patients are often Neurol Ther (2018) 7:13–22 15 unchanged in the fundamental areas of their with increases in the rivastigmine, memantine personality and behaviour, have preserved was introduced. Due to decreased kidney func- insight into their illness, and are therefore tion, the memantine dose was maintained at almost always very grateful for help from their 5 mg daily. caregivers. This makes it easier for the caregivers It is beneﬁcial to try to reach as high a to manage throughout the disease, despite maintenance dose as possible from the begin- heavy physical and working moments, getting ning. Increasing rivastigmine at later stages of up several times during the night and having the disease is neither theoretically nor practi- their social lives restricted. It also minimizes cally fruitful. We usually use rivastigmine due feelings of loneliness for the caregiver. Our to the possibility of bandage administration, patient has a very strong interest in his com- since swallowing difﬁculties due to pharyngeal pany and wishes to continue working, which dysphagia is eventually seen in a large propor- motivates him to meticulously follow all advice tion of these patients . in order to get better. Using acetylcholinesterase inhibitors to ‘economize’ with acetylcholine usually improves the visual hallucinations. We also aim SUCCESSFUL PHARMACOLOGICAL to introduce memantine early. In older patients TREATMENT BASED ON OUR with reduced expected life span, and for whom visual hallucinations are not a main problem, it CLINICAL EXPERIENCE WITH DLB may be efﬁcient to start with memantine since PATIENTS this titration is faster (1 month compared to maybe 6 months with cholinesterase inhibi- Cholinesterase Inhibitor and Memantine tors), and thereafter introduce rivastigmine to ensure that the sufferer gets a chance to beneﬁt According to our experience, it is of utmost from the treatment. We have, together with importance to consider the sequence in which researchers from Norway and England, shown the medication is introduced to the patient. We that memantine improves DLB patients globally start medication with rivastigmine and by improving their quality of life, reducing RBD memantine and, thereafter, the most trouble- as well as improving cognition (mental speed) some symptom is considered and treated [1, 7, 8, 18]. In clinical practice improvement in speciﬁcally. If treatment does not commence some patients’ motor functions can be striking; with rivastigmine or memantine, side effects however, this clinical experience was not con- from medication directed at a single symptom ﬁrmed in our study or in the review by Stinton can provoke symptoms of the DLB disorder et al. . itself, including symptoms that have yet to appear clinically. For example, if you start with L-dopa treatment to alleviate Parkinsonism, Treat the Most Disturbing Symptom nightmares [or REM sleep behaviour disorder (RBD)] and visual hallucinations can be Once rivastigmine and memantine are in place, enhanced; it may also have a negative effect on we can start treating what the patient (and the the blood pressure, thereby aggravating the caregiver) consider to be their worst problem. general state of the patient. If you start treat- This may vary between patients and also for the ment by trying to reduce the visual hallucina- same patient over time. We ﬁnd it helpful to use tions with any kind of neuroleptic, you may risk the Neuropsychiatric Inventory (NPI) , to the life of the patient because of possible neu- determine a symptom proﬁle and decide on the roleptic hypersensitivity, or at the very least sequence of treatment. For example, if halluci- worsen the parkinsonism as well as lower the nations and delusions dominate, this would blood pressure. For our patient rivastigmine was suggest a particular sequence of treatment that initially prescribed, and increased stepwise to would differ if depression and apathy were to the highest dose at 13.3 mg/24 h. In parallel 16 Neurol Ther (2018) 7:13–22 dominate. Important symptoms and signs are nightmares (RBD) interact with nightly hallu- listed below. cinations. Later, at a time of unexpected psy- chological pressure for our patient, the nightmares returned and were more typical of Parkinsonism RBD. They were then treated with mirtazapine If Parkinsonism is the worst problem, a low dose 15 mg, since he also experienced difﬁculties of L-dopa can now be trialled, up to a total dose falling asleep at night. of 300–500 mg/day, especially if we estimate that the cognitive reserve is sufﬁcient. We rec- ommend never using dopamine agonists or catechol-O-methyl transferase (COMT)-in- Fluctuating Cognition hibitors for these patients. Doing so will most Variations in attention and wakefulness are very likely deteriorate their condition with more often expressed as tiredness: sleeping many easily induced confusional episodes, visual hal- hours at night and still needing more than 2 h lucinations and wild dreams. Many DLB sleep during daytime. Episodic confusion is also patients also beneﬁt from physical training, part of this core criterion. It is difﬁcult to treat which seems to maintain their motor functions the ‘unnatural tiredness’, often the most dis- and postpone worsening. Our patient improved tressing symptom these patients experience. in motor function with memantine, which Rivastigmine can assist but is not enough for made it possible for him to undertake and most patients. Increasing the orthostatic blood increase the recommended physical activity. pressure may help some patients. To try to Overall, daily physical activity improved his reduce the overwhelming tiredness in our motor function, but after 2 years a low dose of L- patient, we tried modaﬁnil 50 mg on two dopa was added, which reduced stiffness in the occasions. It was not a pleasant experience for muscles. The cognitive reserve in our patient him: he felt out of control, happened to push a was estimated to be high with a Minimental vase over the table, moved too quickly and State Examination (MMSE) score of 24. We also stumbled, and could not control his temper changed selective serotonin reuptake inhibitors (became irritated and angry). (SSRI) to Serotonin–norepinephrine–reuptake- In an uncontrolled and small preliminary inhibitor (SNRI) partly to reduce Parkinsonism. study of modaﬁnil and armodaﬁnil, an effect was seen on attention and global mental status, but was contradicted in a case report where exacerbation of agitation and psychosis were RBD described [13, 17]. None of the rather few If the most disturbing symptom is RBD with patients we have tried to treat with modaﬁnil acting out of wild dreams, we usually try mir- have responded positively. An alternative is the tazapine, especially if there is a concomitant non-pharmacological approach of treating depressive component. We try starting with a deﬁcient attention and wakefulness by plan- 30 mg dose from the beginning, since the ning activities and rest periods in advance, by reduced wakefulness would otherwise be informing patients that they have to ‘‘pay’’ for enhanced. However, sometimes the sleep com- unusually strenuous activities with increased ponent is the target of treatment, in which case tiredness and a need to sleep extra hours. One 15 mg is used, carefully informing the patient way of preventing confusional episodes and and caregiver about this potential effect. We tiredness is to plan for a regular rest in the often have to complement this treatment with afternoons and not to force the patient to stay melatonin 2 mg, and in exceptional cases awake so as to ﬁt into ‘normal’ sleeping hours clonazepam 1–2 mg. A disadvantage with clon- later. Most often forced wakefulness will result azepam, however, is a further lowering of the in confusional episodes. This strategy was blood pressure. In our patient rivastigmine practised and stressed by both the patient and reduced the hallucinations as well as the his wife as crucial for his improved state. nightmares, which may illustrate how the Neurol Ther (2018) 7:13–22 17 Depression and Anxiety well-being of the patient. We have seen DLB If depression is the most troublesome symptom, patients improve from 15 to 25 points on the it is important to remember that DLB sufferers MMSE, just by reducing blood pressure lowering most likely have a more noradrenalin domi- medication. Therefore, before introducing nated deﬁciency instead of a serotoninergic agents that increase blood pressure, antihyper- deﬁciency, at least according to the neu- tensives or medications with hypotension as a ropathological reports of DLB cases which fre- side effect will have to be reduced. Treating quently describe very few cells in the locus orthostatic hypotension is important as it could coeruleus. With this in mind, venlafaxine be a negative prognostic factor for DLB . It is 75–150 mg is an alternative strategy, sometimes also important to emphasize that classical combined with mirtazapine. Our patient was orthostatic symptoms and signs may not be already on citalopram for depression when he present. As many as 50% of patients do not came to us. We sometimes see that this strategy report any of the typical orthostatic symptoms worsens the motor function and therefore pre- like dizziness, blurred vision, or feelings of fer SNRI. Mirtazapine 15 mg and melatonin fainting . This means that blood pressure 2 mg were introduced to improve sleep patterns measurements must be undertaken in all and to further reduce depressive tendencies. patients when DLB is suspected. Later, venlafaxin 75 mg replaced citalopram Our patient exhibited low and orthostatic and mirtazapine. blood pressure but no falls or signs of dizziness. The same medication, mirtazapine and/or So midodrine was added to the medication, venlafaxin, is the basal treatment for anxiety. which probably contributed to his general Oxazepam is often used concomitantly with improvement. Repeated orthostatic 24 h blood antidepressants in anxiety in other disorders, pressure measurements were performed, and but may in DLB patients aggravate orthostatic the dose of midodrine was adjusted to appro- hypotension and induce falls, and should be priate time points, and eventually terminated avoided if possible. due to increased blood pressure which is not common, however. Listed below are other common symptoms during the course of the DLB disease. While Orthostatic Hypotension none of these symptoms affected our patient, If the blood pressure is low and orthostatic who is the focus of this study, they were mon- (declines more than 20 mmHg systolic or itored during his visits, as is routine with all our 10 mmHg diastolic while in the supine position patients. within three minutes of standing), midodrine is most often the drug of choice. The starting dose is 2.5 mg 1–2 times daily, never given after Dysphagia 18:00 to avoid nightly hypertension. The In one of our studies we showed that DLB maintenance dose can be as high as 30 mg daily. patients have pharyngeal dysphagia, which puts To plan the timing of the dose, we perform a them at risk of aspiration . Very often this is 24 h blood pressure measurement before start- noted as coughing at night or experiencing a ing treatment. It is also beneﬁcial to combine feeling of food getting stuck in the throat the treatment with compression stockings and without being able to clear it. As mentioned provide widely available information about above, this dysphagia could be alleviated by a how to rise from a lying to standing position simple measure—drinking carbohydrate ﬂuid (sitting on the bedside, ﬂexing and extending . However, our patient has been recom- the feet), how to avoid lowering the blood mended to drink carbohydrate ﬂuid, together pressure while standing in line (crossing the with food and medicine, since this action does legs) and how to help the baroreceptors (sleep- not have to be based on an established pha- ing with an extra cushion under the head at ryngeal dysphagia diagnosis. night). These actions often improve the global 18 Neurol Ther (2018) 7:13–22 Nocturia have seen in our studies that in patients with A symptom that is difﬁcult to treat and often MMSE scores of 16–18, there is a steeper decline leads to a situation where continuing to live at and DLB patients survive for a shorter time home with the partner is precluded, is frequent compared with Alzheimer patients) . How- nightly micturition. The partner is often ever, a large European retrospective DLB study exhausted by not getting enough sleep. Some of did not ﬁnd that the deterioration measured by our patients have a good response to mirabe- MMSE was different for DLB compared with AD gron. Anticholinergic medication should be patients . We and others have also seen that avoided since acetylcholine deﬁciency is one of patients with mixed pathologies, DLB and Alz- the main neurochemical features of DLB, which heimer, and lower beta-amyloid and higher tau limits treatment possibilities. Some of our levels in the CSF, signal worse prognosis [3, 10], patients have successfully used desmopressin in as does a more pronounced orthostatic blood low doses. pressure reaction . The course of the disease. We have learned that longer and more pronounced unexpected dete- Hypersalivation riorations are not part of the natural course for With the basic rivastigmine treatment there DLB patients. In these situations, we should might be an ampliﬁcation of hypersalivation, rather search for additive, treatable somatic already a Parkinsonian symptom of the DLB factors, like infections. On innumerable occa- disorder. Hypersalivation can be socially sions, we have managed to reverse deterioration demanding. In several cases we have seen a by treating a urinary infection, and the patient beneﬁcial effect from Botox injections in the has returned to the status quo. On one occa- salivary glands. For those who only suffer from sion, a patient was moved from hospice back to hypersalivation during the night with soaked her usual residence after proper treatment of an pillows, drops of atropine under the tongue infection. have been helpful. Actively Query Particular Symptoms Hypophonia and Signs A Parkinsonistic symptom which sometimes affects social life is hypophonia. It can be alle- viated by auxiliary means such as voice We have noted that many DLB symptoms and reinforcers. signs, such as visual hallucinations, are rarely The actual treatment of our patient is reported voluntarily by sufferers or their carers. described in Table 1. Most probably, this depends on the insight that patients have, as such phenomena suggest something is wrong with them, maybe psychi- Reﬂection on the Prognostic Factors atrically; therefore, they avoid disclosure, at and the Course of the Disease least in the earlier stages of the disease. One strategy to get information about the halluci- To be able to plan the treatment, it is also nations is to start talking about dreams and valuable to reﬂect on prognostic factors and the nightmares, and inform them that many DLB course of the disease. patients in fact believe the persons in their dreams may remain in their consciousness the Clinical Prognostic Factors day after, and that this experience is not a sign Throughout the years we have tried to under- of a psychiatric illness but an expression of the stand what factors affect prognosis and how DLB disorder. intense the treatment can be for the individual. ‘Wild dreams’ or RBD, which may no longer Having a larger cognitive reserve or capacity be present when other symptoms appear, is with relatively better scores on the MMSE may another symptom that has to be actively quer- signal a more favourable prognosis and possibly ied. RBD may be a very early sign, and can permit faster uptitration of the medication. We Neurol Ther (2018) 7:13–22 19 Table 1 Changes of medication over time to alleviate experienced symptoms and introduce basic treatment of Lewy body dementia in the patient discussed in the paper Year MMSE Aim Worst problem Medication (dose) Result score Many years prior ‘Burnout syndrome’ Citalopram (40 mg) 2012 24 Memory problems Donepezil (10 mg) 2014 DLB diagnosed 24 Nightmares (RBD) Mirtazapine (15 mg) Improvement at the Memory Melatonin (2 mg) Clinic 2014 Jun Basal Stiffness Memantine (5 mg) DLB L-dopa (50 mg ? 0 ? 50 mg) 2014 Jul Basal Donepezil, changed to Marked DLB Rivastigmine patch (4.6 mg/ improvement 24 h) No nightmares 2014 Aug Basal Increase rivastigmine (9.5 mg/ DLB 24 h) 2014 Sep 24 h BP: frequent Start etilefrin No effect on recordings below BP Midodrine 100 mmHg systolic 2014 Nov Basal Midodrine 5 mg BP improved DLB ( ? ? 0) Increase rivastigmine 11.3 mg/ 24 h 2015 Jan Very tired, sleeps a lot 10 min walks daily Continuous improvement 2015 May SSRI to Low BP, standing 85/60 Citalopram (20 mg ?) SNRI venlafaxin (37.5 mg) Midodrine increased (5 mg 1 ? 1?0) 2015 Dec Increased stiffness L-Dopa increased Good effect! (50 mg ? 100 mg ? 50 mg) No nightmares Melatonin paused Difﬁculties falling asleep Tries his wife’s zopiclone (7.5 mg)! 2016 Jan 28 BP increased 168/106 Midodrine stopped standing 139/85, 150/96 Increase L-dopa (100 mg 9 3) Worse balance 20 Neurol Ther (2018) 7:13–22 Table 1 continued Year MMSE Aim Worst problem Medication (dose) Result score 2016 Nov 29 Amlodipine by GP BP: supine 139/93 Standing 125/9, 117/89 2017 May 27 Increased unbearable Modaﬁnil (50 mg once) Confusion tiredness 2017 Oct SSRI to Citalopram (20 mg) changed SNRI to venlafaxine (75 mg) appear as early as 5–10 years before other grandson with his school maths; this was his symptoms. We have one patient who experi- very ﬁrst symptom. Therefore, visuospatial dis- enced RBD 40 years before the rest of the dis- ability and difﬁculties with maths and numbers order appeared. Many of the wives of my have to be actively queried. patients experience RBD as shameful that their husbands ‘‘turn into monsters at night time’’ and therefore do not voluntarily report possible CONCLUSION RBD. Disordered attention and wakefulness, In conclusion, DLB is a neurocognitive disorder expressed by many hours of sleep during the even if the patient’s memory is relatively night, often 12–14 h, also has to be queried. The spared, which often misleads on initial presen- reason for its under-reporting may be that the tation. Parkinsonism without tremor means we sufferers often need their carers’ full attention have to physically examine the patient to be when they are awake; therefore, while the DLB able to establish Parkinsonism. DLB patients patient is asleep their carers take the opportu- and their carers may not report visual halluci- nity to fulﬁl household tasks. It is also more nations, disturbed REM sleep or deﬁcient difﬁcult for carers and other surrounding people attention with many hours of sleep during the to understand that something is wrong since night. This puts demands on the health care many DLB patients are intellectually well-pre- professionals to be informed about DLB and to served, especially with respect to memory. ask the right questions. DLB is underdiagnosed, Many of the patient’s incapacities are blamed and should constitute up to 24.4% of all on motor dysfunction, Parkinsonism, even if dementia cases , but is reported only in 3% of visuospatial inability or deﬁcient execution may the patients in the Swedish dementia registry. be equally important reasons. Examples of This is regretful, as correct treatment may sig- visuospatial dysfunction are difﬁculties with niﬁcantly improve the quality of life of these sitting straight on a chair, putting on clothes, patients. serving a drink and managing domestic appli- Among the different cholinergic pharmaco- ances. Difﬁculties with handling numbers in all logical agents evaluated by Stinton et al. , sort of situations are also typical. A university we use rivastigmine which has had beneﬁcial teacher of mathematics came to the clinic effects and rarely adverse events according to because he could not help his 8-year-old Neurol Ther (2018) 7:13–22 21 our experience; although these events were Authorship. All named authors meet the mentioned in their review. Memantine is International Committee of Medical Journal described as being well tolerated but with few Editors (ICMJE) criteria for authorship for this beneﬁts, the latter in contrast to our clinical article, take responsibility for the integrity of experience. This might be due to the fact that the work as a whole, and have given their we start memantine treatment at an earlier approval for this version to be published. stage of the disease compared to the studies. Of Disclosures. Elisabet Londos has nothing to the substances found by the study to have an disclose. effect, we routinely use levodopa and some- times a low dose of clozapine and clonazepam, Compliance with Ethics Guidelines. In- but we have yet to see any positive effect from formed consent was obtained from all partici- modaﬁnil. Our clinical experience is consistent pants for being included in the study. with study ﬁndings that selegiline, olanzapine, quetiapine, risperidone and citalopram do not Open Access. This article is distributed appear to be effective in the treatment of DLB. under the terms of the Creative Commons As our patient and his wife described above, Attribution-NonCommercial 4.0 International there are possibilities for great improvement. License (http://creativecommons.org/licenses/ We have throughout the years seen patients by-nc/4.0/), which permits any noncommer- who were moved from dementia to non-de- cial use, distribution, and reproduction in any mentia wards in nursing homes, patients who medium, provided you give appropriate credit were able to move back home from a nursing to the original author(s) and the source, provide home. One patient at a nursing home, for a link to the Creative Commons license, and example, managed to call an estate agent and indicate if changes were made. bank and bought an apartment for himself since he did not enjoy his room at the nursing home. 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