Cholinergic crisis Treatment of myasthenia with anticholinesterases can be usefully monitored clinically by observation of the pupil (a diameter of 2 mm or less in normal lighting suggests overdose). Overdosage produces a cholinergic crisis, and further drug should be withheld. ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is the most common cause of dementia. Its incidence increases with age. It is estimated that approximately 500 000 people in the USA are affected. The symptoms of Alzheimer’s disease are progressive memory impairment associated with a decline in language, visuospatial function, calculation and judgement. Ultimately, this leads to major behavioural and functional disability. Acetylcholinesterase inhibiting drugs, e.g. donepezil, can slow down the progression of mild and moderate Alzheimer’s disease, but the benefit is pitifully small and only temporary. Clinical trials of other drug therapy, such as oestrogens, non-steroidal anti-inflammatory drugs (NSAIDs), statins, metal chelation and vitamin E, have failed to show conclusive benefit. Depression is commonly associated with Alzheimer’s disease and can be treated with a selective serotonin reuptake inhibitor (SSRI), e.g. sertraline. Antipsychotic drugs and benzodiazepines are sometimes indicated in demented patients for symptoms of psychosis or agitation but their use is associated with an increased risk of stroke. PATHOPHYSIOLOGY Specific pathological changes in the brains of patients with AD can be demonstrated, for example by positron emission tomography (PET) scanning (Figure 21.4). Forty per cent of AD FDG 11 C-PIB 60 50 40 30 20 10 0 3 2 1 0 ALZHEIMER’S DISEASE 131 patients have a positive family history. Histopathology features of AD are the presence of amyloid plaques, neurofibrillary tangles and neuronal loss in the cerebrum. Degeneration of cholinergic neurones has been implicated in the pathogenesis of Alzheimer’s disease. Neurochemically, low levels of acetylcholine are related to damage in the ascending cholinergic tracts of the nucleus basalis of Meynert to the cerebal cortex. Other neurotransmitter systems have also been implicated. The brains of patients with Alzheimer’s disease show a reduction in acetylcholinesterase, the enzyme in the brain that is primarily responsible for the hydrolysis of acetylcholine. This loss is mainly due to the depletion of cholinesterase-positive neurones within the cerebral cortex and basal forebrain. These findings led to pharmacological attempts to augment the cholinergic system by means of cholinesterase inhibitors. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors that are licensed for the treatment of mild to moderate AD. Memantine is an NMDA receptor antagonist and inhibits glutamate transmission. It is licensed for moderate to severe dementia in AD. DONEPEZIL, GALANTAMINE AND RIVASTIGMINE Use Donepezil, galantamine and rivastigmine have been licensed for the treatment of mild to moderate dementia in AD. Only specialists in management of AD should initiate treatment. Regular review through Mini-Mental State Examination with assessment of global, functional and behavioural condition of the patient is necessary to justify continued treatment (Table 21.2). Mechanism of action These drugs are centrally acting, reversible inhibitors of acetylcholinesterase. Galantamine is also a nicotinic receptor agonist. Figure 21.4: PET images of the brain of a 67-year-old healthy control subject (left) and a 79-year-old Alzheimer’s disease patient (right). The top images show 18 FDG uptake, and the bottom images show Pittsburgh Compound-B (PIB) retention. The left column shows lack of PIB retention in the entire grey matter of the healthy subject (bottom left) and normal 18 FDG uptake (top left). Nonspecific PIB retention is seen in the white matter (bottom left). The right column shows high PIB retention most marked in the frontal and temporoparietal cortices of the Alzheimer patient (bottom right) and generalized 18 FDG hypometabolism (top right) (adapted from Klunk WE et al. Annals of Neurology 2004; 55: 306–19).
132 MOVEMENT DISORDERS AND DEGENERATIVE CNS DISEASE Table 21.2: Pharmacokinetics of donepezil, galantamine and rivastigmine Donepezil Galantamine (prolonged release preparation) Rivastigmine Tmax 4 hours 4 hours 1 hour Protein binding 90% 18% 40% CYP3A4 metabolites ✓ ✓ ✓ Plasma t1/2 unknown 70 hours 8 hours �2 hoursa a Cholinesterase inhibition, duration 10 hours. Adverse effects With all three drugs, adverse effects are mainly a consequence of the cholinomimetic mechanism of action and are usually mild and transient. Nausea, vomiting and diarrhoea are common. Fatigue, dizziness, dyspepsia, urinary problems and syncope have been reported. Careful dose titration can improve tolerance. In overdose, a cholinergic crisis may develop including severe nausea, vomiting, abdominal pain, salivation, lacrimation, urination, defaecation, sweating, bradycardia, hypotension, collapse, convulsions and respiratory depression. In addition to supportive treatment, atropine should be administered which reverses most of the effects. Drug interactions Theoretically, donepezil might interact with a number of other drugs that are metabolized by cytochrome P450, but at present there is no clinical evidence that this is important. MEMANTINE Memantine is an NMDA receptor antagonist used in moderate to severe dementia in AD and Parkinson’s disease. The National Institute for Clinical Excellence (NICE) does not recommend its use outside clinical trials. Key points Alzheimer’s disease • The prevalence of Alzheimer’s disease is increasing in ageing populations. • Currently, the principal therapeutic target is reduced cholinergic transmission. • Placebo-controlled studies in patients with mild or moderate Alzheimer’s disease of central cholinesterase inhibitors showed that scores of cognitive function were greater at three to six months in patients treated with the active drug. The clinical importance of this difference is uncertain. • The therapeutic benefits of cholinesterase inhibitors appear to be modest and have not yet been demonstrated to be sustained. Such therapy does not appear to affect underlying disease progression or mortality. Case history A 21-year-old woman was treated with an anti-emetic because of nausea and vomiting secondary to viral labyrinthitis. She received an initial intramuscular dose of 10 mg of metoclopromide and then continued on oral metoclopramide 10 mg three times a day, which relieved her nausea and vomiting. Two days later she was brought into the local Accident and Emergency Department because her husband thought she was having an epileptic fit. Her arms and feet were twitching, her eyes were deviated to the left and her neck was twisted, but she opened her mouth and tried to answer questions. Muscle tone in the limbs was increased. Question What is the diagnosis here and what is the most appropriate and diagnostic acute drug treatment? Answer Her posture, dystonia and head and ocular problems all point to a major dystonia with oculogyric crisis, almost certainly caused by metoclopramide. This side effect is more common in young women on high doses (a similar syndrome can occur with neuroleptics, such as prochlorperazine, used to treat nausea). It is probably due to excessive dopamine blockade centrally in a sensitive patient. It usually resolves within several hours of discontinuing the offending drug, and in mild cases this is all that may be needed. In more severe cases, the treatment of choice is intravenous benztropine or procyclidine (anticholinergic agents), and further doses may be required, given orally. An alternative, equi-effective but less satisfactory therapy because it is not diagnostic is intravenous diazepam. FURTHER READING Citron M. Strategies for disease modification in Alzheimer’s disease. Nature Reviews. Neuroscience 2004; 5: 677–85. Nutt JG, Wooten GF. Diagnosis and initial managements of Parkinson’s disease. New England Journal of Medicine 2005; 353: 1021–7. Richman D, Agius M. Treatment of autoimmune myasthenia gravis. Neurology 2003; 61: 1652–61.