Over 95% of cases of dementia are attributable to Alzheimer’s disease (AD), vascular dementia (VaD), dementia Lewy body (DLB), and frontotemporal dementia (FTD), as well as mixed Alzheimer’s and VaD, and so on. In this chapter we consider some of the rare and unusual causes that account for the remaining 5%. Categorizing them according to aetiological group (degenerative, vascular, and infectious causes, including human prion diseases), we discuss the presentation of these forms and reasons for variations in estimated prevalence rates in the general population. We shall then go on to describe toxic, iatrogenic, nutritional, traumatic, metabolic, neoplastic, and autoimmune causes of dementia. Disorders are graded according to their prevalence, to give an idea of the likelihood of their presentation. Guidance is given on the investigation of uncommon cognitive impairment and dementia. We have tried to avoid repeating information available in the Chapter 3 on the causes of young-onset dementias, but inevitably there is some overlap of material.
Over 95% of cases of dementia are attributable to Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), as well as mixed Alzheimer’s and VaD, and so on. In this chapter we consider some of the rare and unusual causes that account for the remaining 5%. Categorizing them according to aetiological group (degenerative, vascular, and infectious causes, including human prion diseases), we discuss the presentation of these forms and reasons for variations in estimated prevalence rates in the general population. We shall then go on to describe toxic, iatrogenic, nutritional, traumatic, metabolic, neoplastic, and autoimmune causes of dementia. Disorders are graded according to their prevalence, to give an idea of the likelihood of their presentation. Guidance is given on the investigation of uncommon cognitive impairment and dementia. We have tried to avoid repeating information available in Chapter 3 on the causes of young-onset dementias, but inevitably there is some overlap of material.
Dementia is a common and growing problem worldwide. Much is known about its more frequent causes, such as AD, and vascular, Lewy body and FTD, but its numerous rarer forms are less well understood. Reported prevalence rates of these rare forms vary, perhaps owing to inadequate epidemiological studies, regional variations (especially in those with genetic and familial basis), and differences in detection levels and accuracy of diagnosis. However, a European Union project on rarer forms of dementia estimated a prevalence of 5 cases per 10,000 in the community.1
Box 4.1 summarizes the spectrum of the degenerative causes of dementia.
Familial Alzheimer’s disease
Pure hippocampal sclerosis
Frontotemporal lobar degeneration
Primary progressive (non-fluent) aphasia
Progressive supranuclear palsy (SteeIe–Richardson–OIszewsky syndrome)
Multiple system atrophy (Shy–Drager syndrome)
Amyotrophic lateral sclerosis/motor neurone disease (Lou Gehrig’s disease)
Spinocerebellar and Friedreich’s ataxias
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu–Hakola disease)
Familial Alzheimer’s Disease
This rare cause of dementia may mimic AD.3 It is characterized by severe neuronal loss and gliosis of the hippocampus in the absence of changes present in other common dementias (pure hippocampal sclerosis is very rare). Onset is usually in the very old (over-80s). The rate of progression, clinical signs, and symptoms are similar to those of AD, with prominent short-term memory loss. However, behavioural disturbance and subtle neuropsychological deficits also suggest similarities with FTD.4 The cause is unknown, and association with vascular risk factors is inconclusive. Post-mortem examination is required for definitive diagnosis and there is no known treatment.
Frontotemporal dementias are important causes of young-onset dementia and are discussed in Chapter 3.
Corticobasal degeneration affects between 2 and 6 people per 100,000.1 It is a degeneration of the frontoparietal cortical basal ganglia structures and other subcortical nuclei owing to tauopathy. Corticobasal degeneration is similar to that of progressive supranuclear palsy but with higher putaminal involvement and some vermian atrophy of the cerebellum. It is a sporadic progressive disorder with diverse presentations, including dystonia, myoclonus, rigidity that does not respond to L-dopa, cortical sensory loss (alien hand), apraxia, dysphagia, and aphasia. Frontal executive impairment is common; calculation and visuospatial skills are also commonly impaired, but semantic memory is spared and episodic memory loss is less prominent than it is in AD.5 Electroencephalogram (EEG) changes may be indicative and scans show asymmetrical frontoparietal and midbrain atrophy with third ventricular enlargement greater than that seen in Parkinson’s disease.6
Multiple system atrophy is probably more common than was previously thought; estimates have put the prevalence at 16.4 per 100,000 population.7 It is a neurodegenerative disorder with tauopathy. There is usually cerebellar (olivopontine) and striatonigral degeneration. There is progressive autonomic system failure, with orthostatic hypotension causing light-headedness, constipation, urinary incontinence, inability to sweat, and impotence. Other features include severe dysarthria, falls, myoclonic jerks, disruption of the rapid eye movement phase of sleep, and visual problems. Parkinsonism may be present. Blood pressure monitoring and ophthalmology examination should be included. There are abnormal plasma and urinary levels of noradrenaline and its breakdown products. Magnetic resonance imaging (MRI) helps to distinguish it from progressive supranuclear palsy, as there is higher putaminal involvement, and vermian cerebellar atrophy differs from that of Parkinson’s disease.6 Non-specific treatments such as raising the head-end of the bed, increased dietary salt and fluid intake, and tube-feeding are useful. Alpha-adrenergic, salt-retaining steroids (with close monitoring), and L-dopa may be tried.
Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND), has a prevalence of 5–7 per 100,000,8 has multifactorial causation involving over-activity of the immune system. There is familial clustering, with dominant traits of variable penetrance and expressivity, and, rarely, recessive traits. Average age at presentation is mid-50s, but it can present in young adults. Life expectancy is about 3 years from diagnosis. Clinically, both upper and lower neuron signs are present, progressing to spasticity. Clinical signs include diminished fine motor coordination, bulbar signs, dysarthria, dysphagia, abnormal jaw jerk, and parkinsonism. There is an association between MND and FTD; and in MND patients without dementia there may be subtle frontal executive problems. Electromyography and nerve conduction studies are used to confirm denervation of at least three limbs; MRI may show hyperintensities in corticospinal tracts. Riluzole, a glutamate antagonist, has been shown to have a small effect on improving function and life expectancy, although this remains modest.9
Huntington’s disease has been discussed in Chapter 3.
Ataxias are an hereditary group of disorders with a worldwide prevalence of 0.3–3 per 100,000 with regional variations. Friedreich’s ataxia is the most common.10 These disorders are inherited as autosomal dominant (spinocerebellar ataxia types 1, 2, and 3; olivopontocerebellar atrophy; Charcot–Marie–Tooth disease), recessive (Friedreich’s ataxia, ataxia due to vitamin E deficiency), or, rarely, cross-linked.11 There is degeneration of the cerebellum, brainstem, and spinal cord. Early symptoms include unsteady and clumsy motion, and fine incoordination. Progression is associated with pyramidal and extrapyramidal signs, peripheral neuropathy, slow saccadic eye movement (especially in spinocerebellar ataxia type 2), nystagmus, ophthalmoplegia, and optic atrophy. Dementia can be progressive and is mild to moderate in some subtypes (e.g. spinocerebellar ataxia type 2). Executive dysfunction and verbal memory deficits occur in others. Magnetic resonance imaging shows cerebellar atrophy; molecular genetic testing identifies the variant. Management includes genetic counselling, speech therapy, and physical rehabilitation. Ataxia with vitamin E deficiency requires lifelong vitamin E treatment. Benzodiazepines and propranolol may reduce tremor.
This is a very rare disorder of presenile dementia with bone cysts of global distribution. It results from mutations in genes DAP12 and TREM2, which are needed for dendritic maturation. There is localized destruction of adipose tissue, cystic bone lesions, osteoporosis causing spontaneous fractures, and loss of brain white matter owing to progressive sclerosing leukoencephalopathy.12 Clinically, pain occurs in the bony extremities by the third decade, followed by multiple fractures. By the fourth decade, neuropsychiatric symptoms develop, including profound progressive dementia, generalized seizures, and hypofrontality. Neurological examination shows upper motor neurone signs progressing to dyspraxia and dysphasia (similar to AD). Radiography of joints and EEG are useful. Brain scans show cortical atrophy and calcification of the basal ganglia. There is no known treatment.
The vascular causes of dementia have been discussed in Chapter 2. It is worth noting that diffuse subcortical small vessel disease, which is common enough, includes what has previously been called Binswanger’s disease, which presents with subcortical dementia (‘cortical disconnection syndrome’) where psychomotor slowness is the most characteristic feature, along with short-term memory impairment, and significant frontal executive and behavioural problems. Physical problems include parkinsonian features, urinary incontinence, and pseudobulbar palsy. Investigations should include electrocardiogram, blood pressure, blood glucose, and lipid monitoring. Treatment is with selective serotonin reuptake inhibitors for depression and anxiety, and atypical antipsychotics (with caution and only if necessary) for behavioural problems. Management of hypertension, diabetes, and arrhythmias may slow disease progression.
Also discussed in Chapter 2 was cerebral amyloid angiopathy, where cognitive impairment is common and may precede intracerebral haemorrhage. The progress of dementia varies but can be rapid. Raised intracranial pressure should be excluded. There is no specific treatment, but treating cardiovascular risk factors and evacuation of haematomata are indicated if required.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was also mentioned in Chapter 2, but is discussed further here.
With a prevalence of less than 1 per 100,000, cerebral CADASIL is a non-atherosclerotic, non-amyloid cerebral vasculopathy. Silent lacunar infarcts and white matter changes begin by the third decade, about 10 years before neurocognitive signs become apparent. Predominant multiple small deep ischaemic subcortical infarcts lead to VaD. There is mutation of the NOTCH3 gene on chromosome 19. Clinical features include migraine with aura, recurrent transient ischaemic attacks, and subcortical dementia with late-stage urinary incontinence and supranuclear palsy.13 Dementia is global and progressive, with executive dysfunction but with relative preservation of episodic memory. Mean age at onset is the mid-40s. Magnetic resonance imaging shows large areas of leukoencephalopathy with multiple subcortical lacunar infarcts (see imaging for young-onset dementia in Chapter 13). There is no specific treatment. Antiplatelet drugs and statins are used to prevent progression, but they are unlikely to be effective as this is mainly a disease of the arterial media.
Human Prion Diseases
The variety of human prion diseases is shown in Box 4.2.
Fatal familial insomnia
Sporadic Creutzfeldt–Jakob disease (CJD) is the most common form of human prion disease. The worldwide average prevalence of CJD is around 0.1 cases per 100,000 persons; 85% of cases are of the sporadic type.14, 15 This is a poorly understood neurodegenerative disease in which accumulation of prion protein affects the grey matter, with neuronal loss, gliosis, and characteristic spongiform change. Although generally non-hereditary, in a minority of cases the disease is transmitted as an autosomal dominant form owing to mutation of the prion protein gene (PRNP) on chromosome 20. Most cases occur after the fifth decade. A prodromal period with fatigue, headaches, weight loss, and depression is often present. The classic symptom triad comprises rapidly progressing global dementia, myoclonus, and ataxia, along with progressive pyramidal, extra-pyramidal, and cerebellar dysfunctions with gait, visual (leading to blindness), and speech problems. Typically, 1–2 Hz triphasic periodic sharp-wave changes in EEG are present and cerebrospinal fluid (CSF) proteins are raised. Magnetic resonance imaging shows basal ganglia hyperintensities (characteristically in the putamen and caudate). Treatment is symptomatic. Sodium valproate and clonazepam may reduce the severity of movement disorders.
A small fraction of all prion diseases result from inadvertent transmission of CJD between humans, mostly via medical procedures (e.g. contact with surgical instruments, corneal grafts). Spongiform changes and symptoms are similar to those of sporadic CJD, usually with rapid progression. The history of illness is vital for diagnosis. Investigations and treatment are as for sporadic CJD.
Since being identified in 1996, as of 2013, 174 cases have been diagnosed in the UK.16 In its Annual Epidemiological Report for 2016, the European Centre for Disease Prevention and Control reported as follows: ‘For 2016, Italy and the UK each reported a single case of variant CJD. The overall mortality rate remains below 0.01 per 1 million population in this long post-epidemic tail.’17 Variant CJD is caused by transmission of prion protein variants via food originating from cattle. It is distinct from the other types of CJD in its pathology. Individuals with the disease have diffuse vacuolation, with florid plaques that have a dense core and a halo of spongiform change. Early psychiatric symptoms include depression, personality changes, irritability, aggression, along with neurological deficits such as ataxia, chorea, myoclonus, dysaesthesias, and dementia.18 Variant CJD occurs in young adults. Survival time after onset of disease is a year or so longer than in sporadic CJD. The pulvinar sign on MRI scan and positive tonsil biopsies for prion protein (negative in sporadic CJD) are helpful indicators. Electroencephalogram is often normal. Treatment is the same as for sporadic CJD.
Familial CJD accounts for 10–15% of CJD cases. It is unusually frequent in some ethnic groups (e.g. Libyan Jews). It has autosomal dominant inheritance due to PRNP mutations. Its pathological processes, symptoms, investigations, and treatments are similar to those for sporadic CJD, but age at onset is earlier (40–50 years, but as early as 20 for certain PRNP mutations).15 Genetic testing may identify carriers and early/late-onset varieties, so genetic counselling is important.
Fatal familial insomnia is extremely rare. It results from a polymorphism at codon 129 of the prion gene on chromosome 20. There is gliosis and neuronal loss mainly in the thalamus, inferior olives, and to a lesser extent in the cerebellum.19 It is most common in the fourth decade (range 20–70 years). The illness results in progressive insomnia, along with movement disorders such as myoclonus, dysautonomia, inattention, confusion, psychosis (complex hallucination), and dementia (severe memory impairment with relatively preserved intellectual functioning). Death usually occurs within 12 months of onset. Genetic screening and counselling are available and treatment is supportive.
This extremely rare disease results from heterogeneous mutations of a prion gene, associated with multicentric cerebellar amyloid plaque depositions and symptoms of olivopontocerebellar degeneration. There are typical (but fewer) spongiform changes, gliosis, and neuronal loss. Neurofibrillary tangles may be present. Onset is in the third and fourth decades. Clinical presentation varies, with initial signs of cerebellar dysfunction (e.g. clumsiness, ataxia, and dysmetria) progressing to rigidity, hypo-reflexia, and dementia. Extrapyramidal signs, gaze palsies, pseudobulbar palsies, and cortical blindness may occur.2 Death occurs 3–8 years after onset. Electroencephalogram may show characteristic changes and MRI may demonstrate mild cerebral and cerebellar atrophy. Post-mortem examination is confirmatory.
Infectious Causes of Dementia
There is a variety of infective agents that can cause or contribute to dementia, as summarized in Box 4.3.
Progressive multifocal leukoencephalopathy
Subacute sclerosing panencephalitis
The infective agent of Lyme disease is the spirochaete Borrelia burgdorferi, transmitted in tick bites. The disease occurs sporadically in parts of North America, Europe, and Asia, but true prevalence is unknown. Lyme disease typically causes a red rash (erythema migrans) which sometimes has a central clearing, is not itchy, and becomes visible 1–4 weeks after the tick bite. Lyme disease should be considered in patients presenting with subsequent fever, fatigue, muscle/joint pains, cognitive impairment, neurological symptoms (such as facial palsy), cardiac problems (e.g. heart block), or uveitis.20 Lyme disease can be difficult to recognize as it causes many symptoms across multiple systems. Testing for Lyme disease should only occur if there is clinical suspicion, and should not be based on a tick bite alone. Treatment is with antibiotics, the choice of which depends on the symptoms.20
Syphilis infection rates are low in Western Europe. Although no longer very prevalent, untreated neurosyphilis is an important cause of dementia, which can present more than a decade after initial infection.21 Human immunodeficiency virus (HIV)-related neurosyphilis tends to have a poorer outcome. The infective agent is the spirochaete Treponema pallidum. There is diffuse meningovascular inflammation and parenchymal involvement, often associated with brain infarcts and focal neurological deficits. Later stages cause tabes dorsalis, a degeneration of the ascending fibres of the dorsal root ganglia affecting the posterior columns of the spinal cord. Clinical presentation varies, from asymptomatic neurosyphilis, acute meningitis, subacute or chronic meningovascular syphilis, tabes dorsalis to general paralysis of the insane with frontotemporal symptoms. Neuropsychiatric symptoms include apathy, irritability, elation, grandiosity, depression, personality changes, and psychosis (rarely), along with neurological signs such as coarse tremor, ataxia, hyperreflexia, dysarthria, Argyll Robertson pupil, seizures, and late-stage spasticity. An accurate medical and treatment history is vital. Investigations include the Venereal Disease Research Laboratory (VDRL), Rapid Plasma Reagin, T. pallidum haemagglutination, and fluorescent treponemal antibody absorption tests; the last two have good reactivity to tertiary syphilis. Treatment is with high doses of intramuscular penicillin (over 10–14 days), doxycycline, or ceftriaxone. Jarisch–Herxheimer reaction may cause initial worsening of symptoms.
Toxocara canis, the parasitic roundworm of dogs, can infect humans through the widespread dissemination of its ova in the environment. The larvae exhibit a predilection for the host’s central nervous system (CNS), migrating to the brain as infection progresses. Clinically, it may mimic dementia, especially in elderly people. Blood and CSF eosinophilia and positive antibody titre are helpful; treatment with antihelmintic agents such as albendazole reverses cognitive impairment.22
The infective agent Taenia solium is acquired from eating infected meat. This is exceptional in the West but more common in low- and middle-income countries. Central nervous system presentation is very rare and potentially reversible. This may be clinically silent, but usually manifests with neurological symptoms such as headaches, focal signs, seizures, hemiparesis, psychiatric, and cognitive problems. Anaemia is common and stool examination may identify worms. Computed tomography or MRI demonstrates space-occupying lesions. Serological tests have low sensitivity and specificity. Treatment with antihelmintics (e.g. albendazole), antiepileptics (for controlling seizures), and steroids (for raised intracranial pressure) is useful.
Encephalitis is inflammation of the brain parenchyma and can be caused by a number of different microorganisms including viruses, and herpes viruses are the most common cause of viral encephalitis. Encephalitis can also be triggered by the immune system after the infection itself has subsided.
The main agents of viral encephalitis are herpes simplex virus types 1 and 2, Epstein–Barr virus, human herpes virus types 6 and 7 in immunocompetent hosts, and cytomegalovirus and varicellazoster virus in immunocompromised patients. The classic presentation of viral encephalitis includes fever, vomiting, headache, neurological signs, and altered consciousness. Presentations can, however, be more subtle and mimic psychiatric conditions or dementia, with behavioural changes and disorientation. All patients who have a fever and altered behaviour or consciousness should have investigations for a CNS infection. Treatment of viral encephalitis is with acyclovir as well as treatment of associated complications.23
Incident rates of HIV-related dementia have fallen significantly in the West owing to antiretroviral therapy (ART), but the effect of longevity on cognition is still uncertain. Anti-retroviral therapy data show that dementia occurs in 5–15% of untreated patients.24 Opportunistic infections such as Toxoplasma gondii, cryptococcal meningitis, neurosyphilis, tuberculous meningitis, cytomegalovirus encephalitis, increased vascular risk factors, and tumours (e.g. lymphomas) can also contribute to a dementia syndrome. HIV can cause encephalitis, leukoencephalopathy, cerebral vasculitis, and neuronal damage, often leading to cortical atrophy with greater subcortical dementia associated with basal ganglia pathology. Acquired immune deficiency syndrome dementia complex occurs with a very low CD4 count (<200) and raised viral load. Cognitive impairment is usually global and moderately severe. Common associated symptoms are inattention, psychomotor slowing, dysexecutive syndrome, poor verbal memory (impaired recall but not recognition), psychosis, mood, and personality problems. Reversibility of symptoms has improved with newer ART drugs, which have greater CSF penetrability. Intravenous drug misuse is associated with a poorer prognosis.
Adult-onset subacute sclerosing panencephalitis is a very uncommon and delayed sequel to persistent measles infection. The prevalence is greatly reduced in countries with high vaccination levels. It leads to progressive and usually fatal encephalitis. There is astrogliosis, neuronal loss, and demyelination. Mean age at onset is in the early twenties, and the disease occurs predominantly in men. In adults it can mimic a degenerative dementia and usually presents many years after the initial infection, with death occurring within 1–3 years. Early changes may be subtle, with attention and behaviour problems. Characteristic features include dementia, seizures, myoclonus, visual problems, pyramidal, and extrapyramidal signs.25 Subacute sclerosing panencephalitis should be suspected in young patients with dementia and myoclonus. Serum measles antibodies may be detected. There is no established therapy and treatment is supportive; antiepileptics may be useful to control seizures and intraventricular α-interferon appears to be effective.25
We shall now describe other rare and unusual causes of dementia, which we categorize as being of ‘exogenous’ (toxicity, vitamin deficiency, brain damage) or ‘endogenous’ (endocrine and other organ failure, compromised metabolism, neoplasia, autoimmunity) origin. We shall start with exogenous factors (Box 4.4). As in the rest of this chapter, we have not attempted to describe purely medical matters in relation to the conditions we are discussing, whether to do with diagnosis or treatment, but have focued on the psychiatric issues, in particular those that relate to cognitive impairment and dementia. Specialist texts should be consulted for fuller discussion of these conditions and specialist clinical input would be required to manage them.
Heavy metals, e.g. lead, mercury, arsenic, manganese
Organophosphates and pesticides
Medications, e.g. steroids, interferon
Alcohol and recreational drugs
Head Trauma and Diffuse Brain Damage
Dementia pugilistica (‘punch drunk’ syndrome)
Anoxic brain injury/delayed post-anoxic encephalopathy
Chronic subdural haematoma
Dementia caused by heavy metals poisoning is most commonly caused by chronic exposure to lead. Causes of chronic lead poisoning include exposure in industrial workplaces, drinking water supplied through lead pipes, and accidental ingestion, for example by ingesting paint.26
Inorganic forms of lead (e.g. in paint, as well as ground and surface water) typically affect the central and peripheral nervous systems and the haematopoietic, renal, gastrointestinal, and reproductive systems. The rarer organic forms (such as tetraethyl lead used in petroleum products) affect the CNS. Lead poisoning presents with a combination of gastrointestinal, haematological (lead interferes with haemoglobin synthesis), and neurological symptoms, including fatigue, depression, confusion, peripheral neuropathy, cognitive impairment, encephalopathy, and seizures. A grey or bluish black lead line may be visible at the gingival border.
Diagnosis is based on history (particularly occupational exposure), clinical features, and venous blood levels. A blood lead level >10 μg/dL is considered toxic. Normocytic or microcytic anaemia and non-specific red cell basophilic stippling on peripheral blood smears are common.
Treatment with chelating agents such as edentate calcium disodium, dimercaptosuccinic acid, or dimercaprol reduces the body stores of lead.27
Dementia caused by chronic mercury poisoning presents in some industrial workers (mercury occurs in certain batteries, paints, and industrial wastes). Symptoms include peripheral neuropathy, ataxia, and fine tremor, progressing to cerebellar (intention) tremor, choreoathetosis, and dementia. Chronic arsenic ingestion causes confusion, memory loss, peripheral neuropathy, ‘raindrop pigmentation’ of the skin, and transverse white lines on the fingernails (Mae’s lines). Treatment for both mercury and arsenic poisoning is chelation therapy.26
Manganese toxicity has been suggested as a cause of dementia.28 In conjunction with genetic predisposition, manganese exposure might play an important role in causing parkinsonian disturbances, possibly enhancing physiological ageing of the brain.29
Aluminium toxicity (dialysis dementia syndrome) can occur secondary to dialysis using water containing aluminium. The syndrome has been mostly eliminated by the use of deionized water.
Untreated patients can develop progressive encephalopathy, confusion, memory loss, agitation, lethargy, myoclonic jerks, and stupor. Electroencephalogram shows non-specific generalized changes. Post-mortem studies show high brain aluminium content without neurofibrillary tangles or amyloid plaques.
A causal link between aluminium and AD had been suggested, but a direct relationship has not been found.30
It has been suggested that environmental exposure to organophosphates and other pesticides is associated with various neurodegenerative processes.31 There is mounting evidence that chronic moderate exposure to pesticides is neurotoxic and increases the risk of Parkinson’s disease, ALS, mild cognitive impairment (similar to that described in the Gulf War syndrome), and dementia.32
The relationship between lithium and dementia is unclear. Subjective complaints by those taking lithium of mental slowness are not uncommon but a longer-term effect remains controversial. One review found a subtle impairment of psychomotor speed and verbal memory but not of visuospatial ability, attention, or concentration.33 Other studies have suggested that lithium in bipolar affective disorder has a protective effect against dementia, owing to its inhibition of AD pathogenesis.34 Acute lithium toxicity can present with cognitive impairment. Investigations in patients on lithium showing cognitive impairment should include measurement of lithium level and routine blood, renal (to exclude chronic renal failure), and thyroid function tests. Adjunctive thyroid hormone may improve cognitive functioning as thyroid levels are restored.
There is much debate around the relationship between long-term antipsychotic use and cognitive impairment. Observational studies have revealed that long-term use of antipsychotics is associated with smaller brain volume and increased ventricular spaces. Moreover, reduced brain volume has been associated with reduced cognitive performance.35 However, these are observational studies, and confounding by illness course and severity may well account for the association.
It has long been known that anticholinergic medication can impair cognitive function, causing confusion and disorientation. But this was considered a temporary phenomenon which would reverse as soon as the medication was stopped. Even so, anticholinergics have caused dilemmas for clinicians and patients for many years, the classic being the use of antimuscarinic medication (such as oxybutynin) for urinary incontinence or an overactive bladder in an older person with mild cognitive problems. Given a requirement for the long-term use of many such medications, the possibility of resulting increased confusion tips the risk–benefit scale in favour of not using the anticholinergics. But this seemingly condemns the patient to the indignities of, for example, urinary incontinence.
In recent years, however, evidence has accumulated that the resulting confusion may not be reversible and that anticholinergics are associated with dementia. In a study from the USA of 3,434 participants aged 65 years and over with no dementia at the start of the study, it was found that higher cumulative anticholinergic use over 10 years was associated with an increased risk of dementia.36 In a UK study of 40,770 patients aged between 65 and 99 years with a diagnosis of dementia compared to 283,933 controls without dementia, the researchers observed a ‘robust association’ between some classes of anticholinergic drugs (in particular, antidepressants, urological, and antiparkinsonian drugs) and the incidence of future dementia.37 A further UK study looked at exposure to anticholinergic drugs ‘in 58,769 patients with a diagnosis of dementia and 225,574 controls 55 years or older matched by age, sex, general practice, and calendar time’.38 They found a significant increase in the risk of dementia in those taking anticholinergic antidepressants, antiparkinsonian drugs, antipsychotics, bladder antimuscarinic drugs, and antiepileptic drugs.38 These studies, therefore, caution against the prolonged use of anticholinergic drugs in middle age or older people because of the risk of dementia.
Moreover, there is a specific worry about antidepressant medication, which may not solely relate to their anticholinergic properties. In a meta-analysis of observational studies, researchers from Taiwan demonstrated ‘that antidepressant use is significantly associated with an increased risk of developing dementia’.39 The risk was highest for monoamine oxidase inhibitors (relative risk (RR) = 2.791), but was high for tricyclics too (RR=2.131), and was also raised for selective serotonin reuptake inhibitors (RR=1.75).39 As in the case of any anticholinergic drugs, the message is not to avoid antidepressants altogether, but to use them judiciously.
Interferon is used in immunotherapy for treatment of cancer and viral infections and has numerous neuropsychiatric side effects. Neurological effects of interferon alpha are more common in older age groups, in those treated with higher doses, in those with longer treatment duration, and when used in combination with other medications that affect cognition. Patients may exhibit mild to moderate symptoms of frontal subcortical brain dysfunction, including cognitive slowing, apathy, and executive dysfunction. There has been at least one report of a dementia-like syndrome which persisted.40 Neurotoxicity may be mediated through neuroendocrine, neurotransmitter, or cytokine pathways. Neuroimaging studies show decreased prefrontal metabolism with interferon alpha therapy. Opiate antagonists could be helpful in treating the cognitive impairment.41