Lewy Body Disease

Original Editor - Henry Tan, Kevin Lam, Alex Mong, Andrew To

Lead Editors

Definition

Lewy body disease or lewy body dementia (LBD) has been found to be strongly linked to a protein called alpha-synuclein. Abnormal accumulation of this protein in certain regions of the brain cause dramatic cognitive and motor deficits affecting behavior, mood, movement and thinking. LBD is one of the most common causes of dementia along with Alzheimers disease[1].

There are 2 types of LBD generally described in the literature:[2]

1) Dementia with Lewy bodies (DLB) – Cognitive deficits appear within a year of onset of parkinsonism related deficits.
2) Parkinson’s disease with dementia (PDD) – Cognitive deficits appear beyond one year of parkinsonism.

People with either type generally develop similar symptoms as the disease progresses. Distinct Parkinsonian symptoms such as slowness of movement, rigidity, REM sleep behaviour disorder and visual hallucinations can help to distinguish DLB from Alzheimer’s disease.[1]



Epidemiology

LBD is becoming increasingly common, affecting more than 1 million people in the US. Typically thought to be uncommon, it is now believed to be the second most common cause of dementia.[2] Age seems to be the greatest risk factor, typically developing in individuals who are over the age of 50. The disease state on average lasts 5 to 7 years from onset to death with men being affected more than women.[1] A retrospective cohort study found cardiovascular diseases (CVD) as a significant cause of death in older people who have dementia with a relatively shorter survival approximately 4 years after the diagnosis of dementia[3].

Other potential risk factors include:[1]
• Parkinson’s disease
• REM sleep disorder
• Genetics (although only a small genetic link has been found)
• No association between lifestyle and LBD

Clinical Presentation

The clinical features of LBD are the consequence of the blockage of information transfer from the striatum to the cortex, more notably the frontal lobe.

Signs and symptoms include:[4]

  • Recurrent visual hallucinations
  • Visuospatial impairment (Stroop test, Clock face test)
  • Executive function deficits (Nelson Card sort test)
  • Parkinsonian motor features (mild gait impairments, resting tremor)
  • Early extrapyramidal features (dystonia, akathisia, muscle rigidity, bradykinesia, tremor, tardive dyskinesia
  • Fluctuating cognitive impairment (periods of coherence and alertness alternating with sequences of confusion and unresponsiveness)
  • Attentional deficits
  • Poor postural stability
  • Neuroleptic sensitivity
  • Orthostatic hypotension

Pathophysiology

The distinguishing feature of LDB is the aggregation of Lewy bodies inside neurons of the cerebral cortex. Aarsland et al, found that an increase in Lewy bodies in the temporal lobe is associated with early occurrences of visual hallucinations - a hallmark of DLB.[5] Additionally, increased Lewy body densities in the limbic and frontal lobes also correlate strongly with the severity dementia. Although much of DLB remains unsolved, recent research has shed light on potential density-location relationships that have assisted clinicians in diagnosing and managing DLB.[5]

The alpha synuclein protein has been proven to be important in many functions in the brain, particularly at synapses. Alpha synuclein aggregate into clumps called Lewy Bodies within neurons. These Lewy Bodies alter chemicals in the brain and can damage neurons which can eventually lead to death of those neurons.[1]

Postmortem studies have shown development of Lewy Bodies can occur in the substantia nigra, locus corulues, dorsal raphe, substantia innominate and dorsal motor nucleus of cranial nerve X.[6]

Regions of the brain affected by LBD include:
• Cerebral cortex
• Limbic cortex
• Hippocampus
• Midbrain
• Brain stem

Lewybody.png
Source (http://labiotech.eu/major-cns-disease-milestones-in-biotech-2015/)

Diagnostic Procedures

It is difficult to diagnose LBD and due to similiarities with Alzheimer's and Parkinson’s disease symptoms, patients are often misdiagnosed.[7] Best practice in the diagnosis of LBD should include a thorough subjective examination, physical examination and neurological evaluation.

Core features should be identified including fluctuations in cognition, visual hallucinations and any motor parkinsonism. If at least two of these symptoms are present, there is a greater likelihood an indvidual has DLB [2]

Motor Parkinsonism features include rigidity, bradykinesia, masked face, stopped posture and shuffling gait[2]. With changes in cognition, a patient can experience variations in attention and alertness. They can also experience confusion from time to time and have fluctuations in mental abilities and behaviour [2]. If a patient experiences motor parkinsonism more than a year after a diagnosis of DLB, it is more appropriate to diagnose the patient with Parkinson's with dementia instead [2]

Ultimately, the most definitive evidence of LBD is obtained via post mortem autopsies.[7]. Cortical and subcortical atrophy can be observed as well as atrophy of the grey matter of the temporal, frontal, and parietal lobes and the insular cortex with diagnostic imaging of patients with LBD[8]. There can also be volume loss in the hippocampus, amygdala and the basal ganglia, specifically the substantia nigra [8]. There can be atrophy of the nirgrostriatal system and compromised dopamine transporters. This is more commonly seen in PDD [8].

Outcome Measures

The Unified Parkinson’s Disease Rating Scale (UPDRS) was used in a study in the assessment of parkinsonism in patients with Lewy Body Disease. The study suggests that use of the 5-item sub-scale of the UPDRS “provides a reliable and generally applicable instrument for the assessment of parkinsonism in patients with Lewy Body Disease”.[9]

Management

A four-stage approach to the management of Lewy Body Disease has been described, which includes: accurate diagnosis, identification of target symptoms with patient and caregiver, medical interventions; and non-medical interventions. [9]

Medical Management:


A number of medication types have been shown to provide some benefit, however, it is very individualised and may work better for one individual than another.. [7]

Treatment can be categorized based on symptoms: autonomic, cognitive, movement, neuropsychiatric and sleep.

1. Treatment for Autonomic Symptoms[9]

  • Reduction or cessation of antihypertensive medication
  • Salt supplementation
  • Fludrocortisone
  • Domperidone
  • Cholinesterase inhibitors
  • Pyrodostigmine

2. Treatment for Cognitive Symptoms

  • Cholinesterase Inhibitors:

Considered the “standard” treatment for Lewy Body Disease. [7] Cholinesterase inhibitors are used to treat cognitive symptoms that may be present for a patient suffering from LBD. This treatment compares favorably with similar treatment in Alzheimer’s disease, as DLB patients have profound cholinergic dysfunction. Precautions must be reviewed prior to prescribing cholinesterase inhibitors, as these medications may increase risk of bradycardia, nausea, vomiting, diarrhea, anorexia and weight loss. Rivastigmine has the widest evidence base for positive effect in individuals Lewy Body Disease. [9]

  • Memantine

3. Treatment of Movement Symptoms

  • Levodopa/Carbidopa: Lower doses of levodopa are prescribed, as motor symptoms experienced in Lewy Body Disease is less than uncomplicated Parkinson’s disease. [5]
    4. Treatment of Neuropsychiatric Symptoms[9]
  • Cholinesterase Inhibitors
  • Antipsychotic medications (quetiapine, clozapine)

5. Treatment of Sleep Symptoms 

  • Caffeine (for patients without periodic limb movement disorder)
  • Methylphenidate
  • Dextroamphetamine
  • Modafinil
  • Armodafinil
  • Melatonin
  • Rivastigmine
  • Clonazepam

Restless Leg Syndrome and Periodic Limb Movement Disorder: *

  • Cardidopa/Levodopa,
  • Benzodiazepines (i.e. Clonazepam)
  • Alpha-2-delta calcium channel ligands (gabapentin, gabapentin enacarbil, and pregabalin)

    * - The above treatment for restless leg syndrome and periodic limb movement disorder are effective in patients with Parkinson’s Disease. There are no trials of these symptoms in the context of Lewy Body Disease.


Non-Medical Management: 


Physiotherapy for Lewy Body Disease is similar to that of Parkinson’s Disease. It can help manage parkinsonism that is prevalent in LBD by providing intervention which will encourage strengthening and flexibility exercises and gait training. Aerobic exercise should be included to optimise cardiovascular fitness.[7] Physiotherapy is especially helpful in improving balance and postural stability to minimize risk of falls. With the addition of exercise, non-motor symptoms such as cognitive decline, sleep problems and fatigue will also improve. As the disease progresses and the dementia increases, exercise can be hard to do. Therefore, it is important to incorporate exercise in the early and middle stages of Lewy Body Disease.

Tips to help make exercise easier to maintain:[7]

  • Provide visual cues by demonstrating exercises
  • Play upbeat music or music the person enjoys
  • Arrange exercise classes or include the support/care-person
  • Do exercises in sitting
  • Make exercise fun and enjoyable

Resources

https://www.lbda.org/

http://www.parkinson.ca/site/c.kgLNIWODKpF/b.8647145/k.6D4A/Diffuse_Lewy_Body_Disease.htm

http://www.lewybodyjournal.org/

http://www.lewybodyjournal.org/links.html


References

  1. 1.0 1.1 1.2 1.3 1.4 National Institute on Aging. Lewy Body Dementia: Information for Patients, Families, and Professionals. (Accessed 4 May 2017). https://www.nia.nih.gov/alzheimers/publication/lewy-body-dementia/basics-lewy-body-dementia
  2. 2.0 2.1 2.2 2.3 2.4 2.5 McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) Report of the consortium on DLB international workshop. Neurology. 1996 Nov 1;47(5):1113-24. PMID:8909416
  3. Naharci MI, Buyukturan O, Cintosun U, Doruk H, Tasci I. Functional status of older adults with dementia at the end of life: Is there still anything to do?. Indian journal of palliative care. 2019 Apr;25(2):197.
  4. Gnanalingham KK, Byrne EJ, Thornton A, Sambrook MA, Bannister P. Motor and cognitive function in Lewy body dementia: comparison with Alzheimer's and Parkinson'ss. Journal of Neurology, Neurosurgery & Psychiatry. 1997 Mar 1;62(3):243-52. http://jnnp.bmj.com/content/jnnp/62/3/243.full.pdf
  5. 5.0 5.1 5.2 Aarsland, D., Burn, D., Chiu, H., Cohen-Mansfield, J., Dickson D, Dubois B, Duda J, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez O, Machado J, McKeith I, Mintzer J, O’Brien J, Playfer J, Reid W. Dementia with Lewy bodies. The Lancet Neurology, 2004 January; 3:19-28. DOI: http://dx.doi.org/10.1016/S1474-4422(03)00619-7
  6. Crystal, H. A. Dementia With Lewy Bodies. (Accessed 4 May 2017). http://emedicine.medscape.com/article/1135041-overview?pa=cDgRhU%2BPIzR23Dql%2BM7%2B565jaAQt6LN6YC%2BY9393F2Za2VPhjJr4I4RTzfItGaGxWFsk2h6wPa3yDctZJ2JfeiwhCTQq25Ki1mL6i64Z7Vg%3D#showall
  7. 7.0 7.1 7.2 7.3 7.4 7.5 Lewy Body Dementia Association. What is LBD? Available from: https://www.lbda.org/category/3437/what-is-lbd.htm [Accessed May 5, 2017]
  8. 8.0 8.1 8.2 Morra LF, Donovick PJ. Clinical presentation and differential diagnosis of dementia with Lewy bodies: a review. International journal of geriatric psychiatry. 2014 Jun 1;29(6):569-76. DOI: 10.1002/gps.4039
  9. 9.0 9.1 9.2 9.3 9.4 Boot B. P. Comprehensive treatment of dementia with Lewy bodies. Alzheimer’s Research Therapy, 2015 May 29; 7:45. DOI: 10.1186/s13195-015-0128-z