Health

Dementia with Lewy bodies (DLB), also known under a variety of other names including Lewy body dementia, diffuse Lewy body disease, cortical Lewy body disease, and senile dementia of Lewy type, is a type of dementia closely allied to both Alzheimers and Parkinson's Diseases. It is characterized anatomically by the presence of Lewy bodies, clumps of alpha-synuclein and ubiquitin protein in neurons, detectable in post-mortem brain biopsies.[1] Lewy Body dementia affects 1.3 million individuals in the United States alone.

Classification

Dementia with Lewy bodies overlaps clinically with Alzheimer's disease and Parkinson's disease, but is more associated with the latter.[1] With DLB, the loss of cholinergic (acetylcholine-producing) neurons is thought to account for the degradation of cognitive functioning, as in Alzheimer's disease; while the loss of dopaminergic (dopamine-producing) neurons is thought to account for the degradation of motor control, as in Parkinson's disease. Thus, DLB is similar in some ways to both the dementia resulting from Alzheimer's disease and the movement problems of Parkinson's disease. The overlap of neuropathologies and presenting symptoms (cognitive, emotional, and motor) can make an accurate differential diagnosis difficult. In fact, it is often confused in its early stages with Alzheimer's disease and/or vascular dementia (multi-infarct dementia) although, where Alzheimer’s disease usually begins quite gradually, DLB often has a rapid or acute onset, with especially rapid decline in the first few months. DLB tends to progress more quickly than Alzheimer’s disease.[2] Despite the difficulty, a prompt diagnosis of DLB is important because of the risks of sensitivity to neuroleptic drugs and because appropriate treatment of symptoms can improve life for both the person with DLB and their caregivers.[2]

DLB is distinguished from the dementia that sometimes occurs in Parkinson's Disease by the time frame in which dementia symptoms appear relative to Parkinson symptoms.[3] Parkinson's disease with dementia (PDD) would be the diagnosis when dementia onset is more than 1 year after the onset of Parkinson's. DLB is diagnosed when cognitive symptoms begin at the same time or within a year of Parkinson symptoms.

Signs and symptoms

While the specific symptoms in a person with DLB will vary, core features of DLB are: 1) fluctuating cognition with great variations in attention and alertness from day to day and hour to hour 2) recurrent visual hallucinations (observed in 75% of people with DLB), and 3) motor features of Parkinson's. Suggestive symptoms are rapid eye movement(REM)-sleep behavior disorder and abnormalities detected in PET or SPECT scans.[4]

Parkinson's features could include shuffling gait, reduced arm-swing during walking, blank expression (reduced range of facial expression), stiffness of movements, ratchet-like cogwheeling movements; low speech volume, sialorrhea and difficulty swallowing. Tremors are less common in DLB than in Parkinson's disease.[5] DLB patients also often experience problems with orthostasis, including repeated falls, syncope (fainting), and transient loss of consciousness.

One of the most critical and distinctive clinical features is hypersensitivity to neuroleptic and antiemetic medications that affect dopaminergic and cholinergic systems.[6] In the worst cases, a patient treated with these drugs could become catatonic, lose cognitive function and/or develop life-threatening muscle rigidity. Some commonly used drugs which should be used with great caution, if at all, for people with DLB are chlorpromazine, haloperidol, or thioridazine.[2]

Visual hallucinations in people with DLB most commonly involve perception of people or animals that aren't there. Delusions may include reduplicative paramnesia and other elaborate misperceptions or misinterpretations.[7] These hallucinations are not necessarily disturbing and in some cases, the person with DLB may have insight into the hallucinations and even be amused by them or conscious that they are not really there. People with DLB may also have problems with vision, including double vision[2] and misinterpretation of what they see, for example, mistaking a pile of socks for snakes or a clothes closet for the bathroom.[7]

Causes

The causes are not yet well understood, but a genetic link with the PARK11 gene has been described.[8] As with Alzheimer's and Parkinson's diseases, most cases of DLB appear sporadically and DLB is not thought to be a strongly hereditary disease.[6] As with Alzheimer's Disease, DLB risk is heightened with inheritance of the ?4 allele of the apolipoprotein E (APOE).[9]

Pathophysiology

Pathologically, DLB is characterized by the development of abnormal proteinaceous (alpha-synuclein) cytoplasmic inclusions, called Lewy bodies, throughout the brain. These inclusions have similar structural features to "classical" Lewy bodies seen subcortically in Parkinson's disease. Additionally, there is a loss of dopamine-producing neurons (in the substantia nigra) similar to that seen in Parkinson's disease, and a loss of acetylcholine-producing neurons (in the basal nucleus of Meynert and elsewhere) similar to that seen in Alzheimer's disease. Cerebral atrophy (or shrinkage) also occurs as the cerebral cortex degenerates. Autopsy series have revealed that the pathology of DLB is often concomitant with the pathology of Alzheimer's disease. That is, when Lewy body inclusions are found in the cortex, they often co-occur with Alzheimer's disease pathology found primarily in the hippocampus, including: senile plaques (deposited beta-amyloid protein), and granulovacuolar degeneration (grainy deposits within, and a clear zone around hippocampal neurons). Neurofibrillary tangles (abnormally phosphorylated tau protein) are less common in DLB, although they are known to occur.,[10][11][12] It is presently not clear whether DLB is an Alzheimer's variant or a separate disease entity.,,[1][13][14][15]Unlike Alzheimer's Disease, the brain may appear grossly normal with no visible signs of atrophy.[16]

Management

There is no cure for DLB; available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, and caregiving.

Pharmaceutical

Pharmaceutical management, as with Parkinson's disease, involves striking a balance between treating the motor and emotive/cognitive symptoms.

Treatment of the movement portion of the disease can worsen hallucinations and psychosis, while treatment of hallucinations and psychosis can worsen parkinsonian symptoms. Doctors may find that the use of cholinesterase inhibitors represents the treatment of choice for cognitive problems and donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl) may be recommended as a means to help with these problems and to slow or prevent the decline of cognitive function.[2] Reports indicate that Lewy body dementia may be more responsive to donepezil than Alzheimer's disease.[17] Memantine may also be useful.[18] Sinemet may help with movement problems, but in some cases may, like dopamine agonists, tend to aggravate psychosis in people with DLB. Clonazepam may help with Rapid eye movement behavior disorder; table salt or antihypotensive medications may help with fainting and other problems associated with orthostasis. Botulinum toxin injections in the parotid glands may help with sialorrhea. Other medications, such as methylphenidate and modafinil, may improve daytime alertness.[1] Experts advise extreme caution in the use of anti-psychotic medication in people with DLB because of their sensitivity to these agents. When these medications must be used, atypical antipsychotics are preferred to typical antipsychotics; a very low dose should be tried initially and escalated only slowly; and patients should be carefully monitored for bad reactions to the drugs.

Due to hypersensitivity to neuroleptics prevention of DLB patients taking this drugs is of great importance. People with DLB are at risk for Neuroleptic Malignant Syndrome, a life-threatening illness, because of their sensitivity to these medications, especially the older Typical antipsychotics such as haloperidol. Other medications, including drugs for urinary incontinence and the antihistamine medication Benadryl can also exacerbate dementia.

Caregiving

Because DLB has no cure, it gradually renders people incapable of tending to their own needs. Caregiving is thus very important and must be carefully managed over the course of the disease. Caring for people with DLB involves adapting the home environment, schedule, activities, and communications to accommodate declining cognitive skills and parkinsonian symptoms.[7]

People with DLB may swing dramatically between good days—high alertness and few cognitive or movement problems—and bad days, and the level of care they need may thus vary widely and unpredictably. Sharp changes in behavior may be due to the day-to-day variability of DLB, but they may also be triggered by changes in the schedule or home environment, or by physical problems, such as constipation, dehydration, bladder infection, injuries from falls and other problems that the person with DLB may not be able to convey to caregivers. Potential physical problems should always be checked out when a person with DLB becomes agitated.

Especially when hallucinations and delusions are not dangerous or troubling to the person with DLB, it may be best for caregivers not to disabuse patients of them. Often the best approach may be benign neglect—acknowledging, but not encouraging or agreeing. Trying to talk the DLB patient out of his delusion may be frustrating to caregivers and discouraging to patients, sometimes provoking anger or dejection. When misperceptions, hallucinations, and the behaviors stemming from these become troublesome, caregivers should try to identify and eliminate environmental triggers, and perhaps offer cues or "therapeutic white lies" to steer patients out of trouble. Doctors may prescribe low doses of atypical antipsychotics, such as quetiapine for psychosis and agitation in DLB. A small clinical trial found that about half of DLB patients treated with low doses of quetiapine experienced significant reduction in these symptoms. Unfortunately, several participants in the study had to discontinue treatment because of side-effects—excessive daytime sleepiness or orthostatic hypotension.[3]

Changes in the schedule or environment, delusions, hallucinations, misperceptions, and sleep problems may also trigger behavior changes. It can help people with DLB to encourage exercise; simplify the visual environment; stick to a routine; and avoid asking too much (or too little) of them. Speaking slowly and sticking to essential information improves communication. The potential for visual misperception and hallucinations, in addition to the risk of abrupt and dramatic swings in cognition and motor impairment should put families on alert to the dangers of driving with DLB.[9]

Epidemiology

Current estimates are that about 60 to 75% of diagnosed dementias are of the Alzheimer's and mixed (Alzheimer's and vascular dementia) type, 10 to 15% are Lewy body type, with the remaining types being of an entire spectrum of dementias including frontotemporal lobar degeneration, alcoholic dementia, pure vascular dementia, etc. It is slightly more prevalent in men than women.[9]

History

Frederic Lewy (1885–1950) was first to discover the abnormal protein deposits ("Lewy body inclusions") in the early 1900s.[19] Dementia with Lewy bodies only started to be diagnosed in the mid-1990s after the discovery of alpha-synuclein staining first highlighted Lewy bodies in the cortex of post-mortem brains of a subset of dementia patients.[6] Because it was only recently discovered, DLB is not a recognized diagnosis in DSM-IV, which was published in 1994. It is, however, briefly mentioned in the DSM-IV-TR (published in 2000) under Dementia Due to Other General Medical Conditions. In 1996, a consortium of scientists initially proposed and later revised diagnostic guidelines.

Attention was drawn to DLB following the 2008 death of actress Estelle Getty, who had previously been diagnosed with both Parkinson's Disease and Alzheimer's Disease before her true condition was discovered. Fellow Golden Girls cast members noted that years earlier, Getty had severe trouble remembering her lines during the filming of the show.