Lewy Body Disease

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

Lead Editors  

Definition

Lewy Bodies were first discovered by a German neurologist in 1912, Dr. Friederich Lewy. Lewy body disease/dementia (LBD) has since been 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, other causes include: Alzheimer’s, stroke, brain tumours and Parkinson’s.

There are 2 types of LBD generally described in the literature based on an arbitrary “1-year rule”:
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. To further complicate things, individuals with DLB may present as having Alzheimer’s disease. However, distinct symptoms such as: slowness of movement, rigidity, REM sleep behavior disorder and visual hallucinations can help distinguish DLB from Alzheimer’s disease.

Clinically Relevant Anatomy

Although not fully understood, alpha synuclein has been noted to be important to many functions in the brain, particularly at synapses between neurons in the brain. 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 in the brain.

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

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

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. (Mckeith) Age seems to be the greatest risk factor, typically developing in individuals who are over the age of 50. Although it varies greatly (2 to 20 years), the disease on average lasts 5 to 7 years from onset to death with men being affected more than women.

Other potential risk factors include:
• Parkinson’s disease
• REM sleep disorder
• Genetics (although only a small genetic link has been found)
• No association between lifestyle and LBD, but a healthy and active lifestyle may decrease ones chances of developing age related dementias

Clinical Presentation

The clinical features of Lewy body disease are mainly a consequence in the blockage of information transfer from the striatum to the cortex, more notably the frontal lobe.

Signs and symptoms of LBD:

• 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 dementia with Lewy bodies is the aggregation and findings of these Lewy bodies inside neurons of the cerebral cortex. Despite the numerous cases of patients with dementia, the pathology regarding Lewy bodies is still unclear as 3-10% of elderly individuals possess Lewy bodies but display no signs or symptoms. However, with patients whom are indeed symptomatic, relationships have been drawn demonstrating a link between lewy bodies and presenting symptoms. Recent research by Aarsland et al, has found that an increase in Lewy bodies in the temporal lobe is associated with early occurrences of visual hallucinations - a hallmark of DLB. In addition, 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.

Diagnostic Procedures

Lewy Body Disease (LBD) can have two forms of clinical diagnoses which are dementia with Lewy bodies and Parkinson’s disease dementia . There are many different diagnostic tools that can be used to diagnose an individual with Lewy body Disease. For every patient that gets diagnosed with LBD, it varies with different types of symptoms that they experience. Symptoms may change from day to day or hour to hour .

It is difficult to diagnose Lewy Body Disease with dementia because it shows similar signs and symptoms to those of Alzheimer and Parkinson’s disease. Therefore LBD can sometimes be missed when diagnosing an individual . But overall, when individuals progress and develop more symptoms of LBD then it becomes easier to diagnosis.
To diagnosis the type of LBD, physical and neurological evaluations are used and a thorough patient interview is done. For example,

• Medical history (past and current diseases and disorders)
• Medications
• Movement evaluation
• Current symptoms
• Social history
• Functional abilities
• Cognitive abilities (attention, language, memory, visual)
• Brain imaging (CT or MRI)
• Blood tests

Ultimately, all these evaluations can’t provide a conclusive diagnosis of LBD. The only way to confirm if an individual has LBD is to have a post mortem autopsy of their brain . With clinical imaging, cortical and subcortical atrophy can be noticeable with LBD. Atrophy can also be seen in the grey matter of the temporal, frontal, and parietal lobes and the insular cortex in an individual with LBD . There can also be volume loss in the hippocampus, amygdala, and the basal ganglia specifically the substantia nigra . In particular with Parkinson disease dementia, there can be atrophy of the nirgrostriatal system and also compromised dopamine transporters .

Clinical Diagnosis of DLB:
To make a diagnosis of dementia with lewy bodies, it has to have one of the core features which are fluctuation in cognition, visual hallucinations, and motor parkinsonism If two are present, a higher case can be made for a patient with DLB.

With changes in cognition, a patient can experience variations in attention and alertness. They can also experience confusion from time to time and can have changes in fluctuation in mental abilities and behaviour . The changes can occur from day to day and can vary in amplitude for a patient experiencing these cognitive changes.

With motor parkinsonism, it is usually mild with patients with DLB. Some of the features are rigidity, bradykinesia, masked face, stooped posture, and shuffling gait . A patient can have a mix of these features associated with motor parkinsonism. If a patient experiences motor parkinsonism more than a year after a diagnosis of DLB, it is more appropriately to diagnose the patient with Parkinson's with dementia instead .

Furthermore, there are suggestive secondary features that can exist with a patient with DLB. If the one of the core features exist with an existing secondary feature, the diagnosis of DLB is very likely .

Suggestive Features:

• REM sleep behaviour disorder
• Severe neuroleptic sensitivity
• Low dopamine transporter uptake in basal ganglia

Moreover, there are other features that DLB can show but are not diagnostic specificity .

• Unexplained loss of consciousness
• Falls and syncope
• Severe autonomic dysfunction
• Systematized delusions

Clinical Diagnosis of PDD:
One of the core features of developing Parkinson’s disease dementia is having idiopathic PD before getting dementia and to have a confirmed diagnosis of Parkinson disease . Also individuals with PDD will have a decreased global cognitive impairment that disrupts daily life. They will present with a impairment of one of the cognitive domains which are attention, executive function, visual abilities, and memory . The tests to evaluate the cognitive domains are described in Table 2 in .

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. This study, conducted by Ballard, McKeith, Burn, Harrison, O’Brien, Lowery, Campbell, Perry & Ince assessed 73 patients using the UPDRS and staged using the Hoehn & Yahr system. They suggest that a 5-item subscale of the UPDRS be used as it “provides a reliable and generally applicable instrument for the assessment of parkinsonism in [patients with Lewy Body Disease]”.

Management / Interventions

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 carer, medical interventions; and non-medical interventions. 

Medical Management:
Medications have been shown to provide some benefit, however, it is very individualized. A medication prescription may work better for an individual than for another one. 

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

1. Autonomic Symptoms

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

2. Cognitive Symptoms

• Cholinesterase Inhibitors:

Considered the “standard” treatment for Lewy Body Disease.  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. 

• Memantine

3. Movement Symptoms 
Levodopa/Carbidopa is most useful in patients with Lewy Body Disease that experience parkinsonism without neuropsychiatric symptoms.  Lower doses of levodopa are prescribed, as motor symptoms experienced in Lewy Body Disease is less than uncomplicated Parkinson’s disease. 

4. Neuropsychiatric Symptoms

• Cholinesterase Inhibitors
• Antipsychotic medications (quetiapine, clozapine)

5. Sleep Symptoms 
Excessive daytime sleepiness, rapid eye movement sleep behaviour disorder (RBD), restless leg syndrome and periodic limb movement disorder are very common with synuclein disorders. These symptoms can be quite responsive to treatment.

    Excessive Daytime Sleepiness:

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

    RBD:

• 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 treatments and interventions, which include strengthening and flexibility exercises and gait training. Aerobic exercise can be implemented to increase cardiovascular fitness as well. 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 to help maintain health.

Tips to help make exercise easier to maintain:

• 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

Individuals may also benefit from occupational therapy, speech language therapy, and psychotherapy.

Differential Diagnosis

There are many similar diseases and disorders similar to Lewy body dementia. LBD is a form of dementia but there many different forms of dementia. For example, Alzheimer’s disease is another form of dementia. Those symptoms include progressive loss of memory, regression of cognitive dysfunction (thinking and judgement), depression, personality changes and disorientation of time and place . An individual can develop Alzheimer’s disease and then progress to express core features of dementia with Lewy bodies. The difference between Lewy body Disease with dementia and Alzheimer’s is unpredictable cognitive abilities and attention, changes in movement patterns, visual hallunications, and REM sleep behaviour disorder .

With Parkinson with dementia, it often starts with a movement disorder that leads to the diagnose of Parkinson disease then the core the features of Parkinson with dementia start to appear.

Other forms of dementia that are similar to LBD are vascular dementia and frontotemporal dementia. Vascular dementia is when a stroke occurs within the brain which causes decrease in oxygen in the brain and symptoms of disorientation, walking difficulties, shuffling gait, and inappropriate behaviour . With frontotemporal dementia, the common symptoms are changes in personality and behaviour, language and speech impairments and movement changes .

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

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