Further rare and unusual dementias Susham Gupta, Olivia Fiertag, Thanakumar Thanulingam, Elena Ros, Bryan Strange and James Warner APT 2012, 18:67-77. Access the most recent version at DOI: 10.1192/apt.bp.107.004804

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Further rare and unusual dementias ARTICLE Susham Gupta, Olivia Fiertag, Thanakumar Thanulingam, Elena Ros, Bryan Strange & James Warner

Toxicity Susham Gupta is a consultant Summary psychiatrist working for the East In the second of two articles on rare causes of Heavy metals London NHS Foundation Trust. dementia, the authors describe toxic, iatrogenic, Olivia Fiertag is a specialty Lead registrar (ST6) for Central and North nutritional, traumatic, metabolic, neoplastic and West London NHS Foundation autoimmune causes of dementia. Disorders are Dementia caused by heavy metals poisoning is most commonly due to chronic exposure to lead. Trust and Honorary Lecturer for graded according to their prevalence, to give an the Academic Unit of Child and idea of the likelihood of their presentation. Guid- Causes of chronic lead poisoning include exposure Adolescent Psychiatry, Imperial ance is given on the investigation of uncommon in industrial workplaces, drinking water supplied College London. Thanakumar cognitive impairment and dementia, especially in through lead pipes and accidental ingestion, for Thanulingam is a specialty doctor at West Middlesex University early-onset illness. example by ingesting paint (Wills 2006). Hospital, Middlesex. Elena Ros is Inorganic forms of lead (for example, in paint, Declaration of interest a staff grade doctor in older adult and ground and surface water) typically affect the psychiatry at South Kensington None. central and peripheral nervous systems and the and Chelsea Mental Health Centre, London. Bryan Strange haematopoietic, renal, gastrointestinal and repro­ is Director of the Laboratory for The number of people affected by dementia contin­ ductive systems. The rarer organic forms (such as Clinical Neuroscience, Centre for ues to rise year on year. A large variety of factors tetraethyl lead used in petroleum products) affect Biomedical Technology, Universidad the central nervous system (CNS). Lead poisoning Politécnica de Madrid, Madrid, can lead to this progressive, debilitating condition Spain. James Warner is a and understanding these is vital in addressing this presents with a combination of gastrointestinal, consultant and honorary senior growing problem. The most common causes of haematological (lead interferes with haemoglobin lecturer in older adult psychiatry dementia, such as Alzheimer’s disease and Lewy synthesis) and neurological symptoms, including at St Charles Hospital, London. fatigue, depression, confusion, peripheral neuro­ Correspondence Dr Susham body disease, account for 95% of cases and have Gupta, Nightingale House, St been widely researched. However, it is important pathy, cognitive impairment, encephalopathy and Charles Hospital, Exmoor Street, not to forget the rarer causes, which account for seizures. A gray or bluish black lead line may be London W10 6DZ, UK. Email: the remaining 5%. They affect a small but equally visible at the gingival border. [email protected] important patient group and very little is written Diagnosis is based on history, clinical features about them in the literature. and venous blood levels. A blood lead level Rare and unusual causes of dementia are proportionally more common in people under 65 Box 1 Exogenous causes of rare dementias † years of age.† They often present first to neurolo­ Diaqnosis and management gists, especially if the patients are younger and of dementia in younger adults Toxicity are discussed in Advances in have physical symptoms. However, mental health • Heavy metals, e.g. lead, mercury, arsenic, manganese Jefferies K, Agrawal N (2009) Early- services are sometimes involved before neurology, and aluminium onset dementia, 15: 380–388. Ed. because of early presentation with mood or • Organophosphates and pesticides psychotic symptoms or behavioural disturbances. • Medications, e.g. steroids, interferon Psychiatric teams may be involved at various stages of assessment and management, and in • Alcohol and recreational drugs some situations they are the first point of contact Vitamin deficiency for the patient, for example through young-onset • Thiamin dementia services or liaison psychiatry. • Folate In a previous issue of Advances, we described • Vitamin B rare dementias with degenerative, vascular, 12 prion and infectious causes (Gupta 2009). Here Head trauma and diffuse brain damage we will describe other rare and unusual causes • Dementia pugilistica (‘punch drunk’ syndrome) of dementia, which we might categorise as being • Anoxic brain injury/delayed post-anoxic encephalopathy of ‘exogenous’ (toxicity, vitamin deficiency, • Head injury brain damage) or ‘endogenous’ (endocrine and other organ failure, compromised metabolism, • Normal-pressure hydrocephalus neoplasia, autoimmunity) origin. We will start • Chronic subdural haematoma with exogenous factors (Box 1).

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>10 mg/dL is considered toxic. Normocytic or Medications microcytic anaemia and non-specific red cell Lithium basophilic stippling on peripheral blood smears are common. The relationship between lithium and dementia Treatment with chelating agents such as eden­ is unclear. Subjective complaints by those taking tate calcium disodium, dimercapto­succinic acid lithium of mental slowness are not uncommon but (DMSA) or dimercaprol reduces the body stores of a longer-term effect remains controversial. One lead (Chisolm 1990). review found a subtle impairment of psychomotor speed and verbal memory but not of visuospatial Mercury, arsenic and manganese ability, attention or concentration (Pachet 2003). Other studies have suggested that lithium in Dementia caused by chronic mercury poisoning bipolar affective disorder has a protective effect presents in some industrial workers (mercury against dementia, owing to its inhibition of occurs in certain batteries, paints and industrial Alzheimer’s disease pathogenesis (Nunes 2007). wastes). Symptoms include peripheral neuro­pathy, Acute lithium toxicity can present with cognitive ataxia and fine tremor, progressing to cerebellar impairment. Investigations in patients on lithium (intention) tremor, choreoathetosis and dementia. showing cognitive impairment should include Chronic arsenic ingestion causes confusion, measurement of lithium level and routine blood, memory loss, peripheral neuropathy, ‘raindrop renal (to exclude chronic renal failure) and thyroid pigmentation’ of the skin and transverse white function tests. Adjunctive thyroid hormone may lines on the fingernails (Mae’s lines). Treatment for improve cognitive functioning as thyroid levels are both mercury and arsenic poisoning is chelation restored. therapy (Wills 2006). Manganese toxicity has been suggested as a cause Interferon of dementia (Dobson 2004). In conjunction with genetic predisposition, manganese exposure might Interferon is used in immunotherapy for treatment play an important role in causing Parkinsonian of cancer and viral infections. Neurological effects disturbances, possibly enhancing physiological of interferon alpha are more common in older age ageing of the brain (Zatta 2003). groups, in those treated with higher doses, in those with longer treatment duration, and when used in Aluminium combination with other medications that affect Aluminium toxicity (dialysis dementia syndrome) cognition (Merimsky 1992). Patients may exhibit can occur secondary to dialysis using water mild to moderate symptoms of frontal subcortical containing aluminium. The syndrome has been brain dysfunction, including cognitive slowing, mostly eliminated by the use of deionised water. apathy and executive dysfunction. Neurotoxicity Untreated patients can develop progressive may be mediated through neuroendocrine, neuro­ encephalopathy, confusion, memory loss, transmitter or cytokine pathways. Neuroimaging agitation, lethargy, myoclonic jerks and stupor. studies show decreased prefrontal metabolism with Electroencephalography (EEG) shows non- interferon alpha therapy. Opiate antagonists could specific generalised changes. Post-mortem studies be helpful in treating the cognitive impairment show high brain aluminium content without (Valentine 1995). neurofibrillary tangles or amyloid plaques. A causal link between aluminium and Alz­ Steroids heimer’s disease had been suggested, but a direct Iatrogenic glucocorticosteroid dementia syndrome relationship has not been found (Campbell 2002). is often unrecognised but occurs in about 1 in 250 people treated with steroids (Varney 1984) and is Organophosphates and pesticides more common in the elderly. The syndrome may

‡Articles of related interest in It has been suggested that environmental exposure reflect steroid neurotoxicity. Glucocorticosteroids Advances include: Davies R, Ahmed to organophosphates and other pesticides is may affect hippocampal volume (Wolkowitz G, Freer T (2000) Chronic exposure associated with various neurodegenerative 2004). Clinically, there is transient impairment of to organophosphates: background processes (Kamel 2004). There is mounting attention, concentration and memory. Cushingoid and clinical picture, 6: 187–192. Davies R, Ahmed G, Freer T (2000) evidence that chronic moderate exposure to features such as facial puffiness and weight gain Psychiatric aspects of chronic pesticides is neurotoxic and increases the risk may be present. Diagnosis requires a history of exposure to organophosphates: of Parkinson’s disease, amyotrophic lateral glucocorticosteroid use and cortisol assay. Symp­ diagnosis and management, 6: 356– sclerosis, mild cognitive impairment (similar to toms are usually reversible with discontinuation 361. Tarn M, Greenberg N, Wessely S (2008) Gulf War syndrome – has it that described in the Gulf War syndrome) and but in rare cases problems may initially worsen gone away? 14: 414–422. Ed. dementia (Hayden 2010).‡ or persist.

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Alcohol and recreational drugs Vitamin B12 deficiency

Heavy use of alcohol and tobacco, both legal, are Vitamin B12 deficiency can be caused by inade­ known to have long-term effects on cognition and quate intake (e.g. in the vegan diet), malabsorption contribute to development of dementia (Hulse due to defective release of gastric intrinsic factor 2005). Chronic heavy alcohol consumption can (gastric achlorhydria, partial gastrectomy), inad­ cause acute Wernicke encephalopathy, followed by equate production of intrinsic factor (pernicious Korsakoff syndrome or alcohol-related dementia anaemia, total gastrectomy), disorders of the (Gupta 2008). However, light to moderate alcohol terminal ileum (tropical and non-tropical spruce, use may have a protective effect on cognition. intestinal resection), competition for cobalamin A few studies (e.g. Rosselli 1996; Hulse 2005) (fish tapeworm, ‘blind loop’ syndrome), drugs have looked at the cognitive side-effects of drugs (colchicines, neomycin) and Crohn’s disease. such as cannabis, ecstasy and cocaine. Some The mechanism of neurological damage may have linked them with various types of cognitive be related to S-adenosylmethionine deficiency. impairment (both short-term and chronic), but Damage to cerebral myelinated fibres may also evidence to suggest direct causality is still not cause dementia. Neurological complications conclusive. Polysubstance use and concomitant include sensory neuropathy (more common in the use of alcohol might compound the problem. upper limbs), myelopathy, optic nerve dysfunction, positive Romberg’s test and altered cognition. Vitamin deficiency Spinal cord involvement may occur. Blood tests may show low vitamin B level, megaloblastic Niacin deficiency (pellagra) 12 anaemia, macro­cytosis and target cells, but Pellagra is mostly found in parts of the world with neuro­logical dysfunction can occur with normal niacin- or tryptophan-poor diets. In the West, it haematological parameters (Wills 2006). is most common in alcoholism, Hartnup disease Early treatment with parenteral vitamin B12 (a congenital defect in tryptophan absorption) stops progression but rarely reverses advanced and carcinoid syndrome (increased conversion of damage to the nervous system. In cases of both hydroxytryptophan to serotonin). folate and vitamin B12 deficiencies, the latter The classic presentation includes dementia, should be replaced first, to prevent precipitation of haemorrhage, dermatitis (Casal collar – dermatitis subacute combined degeneration of the umbilical around the neck) and diarrhoea. Myoclonus, cord. ataxia and seizures may also occur (Wills 2006). The diagnosis is based on detection of low levels Head trauma and diffuse brain damage of the urinary metabolites 2-methylnicotinamide and 2-pyridone. Treatment is with oral niacin. Dementia pugilistica (‘punch drunk’ syndrome) Dementia pugilistica, caused by recurrent head Folate deficiency trauma, is mostly found in boxing, affecting Congenital errors of folate transport and metabo­ about 20% of professional boxers. Symptoms are lism produce developmental delay, cognitive progressive and begin late (even many years after deterioration, motor and gait abnormality, retirement). Severity depends on length of career seizures, and vascular and demyelinating and number of bouts fought. There is profound changes. Deficiency is caused by inadequate loss of pigmented neurons in the substantia nigra, intake, increased requirements, malabsorption without Lewy bodies (Fleminger 2003). The ex­ tent of dementia is variable, with slow progression. and impaired metabolism. Folate and vitamin B12 deficiency both lead to impaired methylation and The syndrome is characterised by extrapyramidal accumulation of homocysteine. In Alzheimer’s symptoms, ataxia, intention tremor, and cognitive disease, high plasma homocysteine levels are and personality change, which help to differentiate associated with more rapid atrophy of the medial it from Alzheimer’s disease. There is progressive temporal lobes (Clarke 1998). social decline. Treatment with drugs for Alzhei­ Patients may present with peripheral neuro­ mer’s disease or Parkinsonism may be useful. pathy, depression, apathy, withdrawal and mild to moderate dementia. Investigations Anoxic brain injury/delayed post-anoxic show megaloblastic anaemia, low serum and encephalopathy cerebrospinal fluid (CSF) folate and raised Severe cerebral hypoxia is usually due to carbon homocysteine. Neuropsychological symptoms monoxide poisoning, cardiac and respiratory arrest respond much more slowly to folate replacement and attempted hanging. Most patients with carbon than do haematological symptoms. monoxide poisoning recover well, but 10–30%

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develop delayed neuropsychiatric sequelae such as prominent memory loss and bradyphrenia. Cortical cognitive and personality changes, incontinence, features such as aphasia, agnosia and apraxia are dementia and psychosis (Ernst 1998). About 10% generally absent. Computed tomography (CT) or develop Parkinsonism (Choi 2002). Memory im­ MRI show ventricular enlargement, a prominent pairment is probably due to hippocampal changes flow void in the aqueduct and third ventricle (the (Zola-Morgan 1986). Computed tomography ‘jet sign’) and rounding of the frontal horns. In and diffusion weighted magnetic resonance 50% of cases, EEG shows beta oscillations with imaging (MRI) show low density in the cerebral bursts of monorhythmic bilateral theta and delta white matter and lesions in the globus pallidus. waves. Lumbar puncture to measure cerebrospinal Levodopa and anticholinergic drugs are unlikely fluid pressure is considered the diagnostic gold to reverse Parkinsonian features. standard, but it has a high incidence of false negatives. Insertion of a ventriculoperitoneal shunt Head injury improves symptoms in 30–40% of patients, but Acute head injury with loss of consciousness can with a relatively high incidence of complications cause anterograde and retrograde amnesia. The such as strokes or seizures. relationship between remote head injury and dementia is unclear. One large study found that Chronic subdural haematoma mild head trauma did not increase the risk of Chronic subdural haematoma is a common dementia or Alzheimer’s disease in older people treatable cause of dementia, with an annual (Mehta 1999). However, other studies have population prevalence of between 1.2 and 7.3 per suggested that previous head trauma is associated 100 000 (Fogelholm 1975) and a male to female with risk of developing Alzheimer’s disease ratio of 2:1. Older individuals with cerebral (Fleminger 2003). atrophy are vulnerable and 25–50% of patients have no identifiable history of head trauma Normal-pressure hydrocephalus (spontaneous or idiopathic subdural haematoma). Normal-pressure hydrocephalus is seen in 6–10% Risk factors include chronic alcoholism, epilepsy, of all dementia patients (Alzheimer Europe 2009). arachnoid cyst, coagulopathy, anticoagulation The pathophysiology is unclear but there is a therapy and cardiovascular disease. Clinical possible cerebrovascular role. The classic triad presentation is often insidious, with altered includes: (a) early gait disturbance characterised consciousness, focal neurological deficits (subtle by proximal weakness and short, shuffling, changes to hemiparesis), headache, gait and broad-based gait; (b) urinary incontinence; and (c) balance abnormalities and seizures. Brain dementia – predominantly subcortical with frontal scans help diagnosis. Treatment is by surgical lobe involvement in later stages, characterised by evacuation. Patients with chronic alcoholism and pneumocephalus have poor outcomes. We will now examine various ‘endogenous’ Box 2 Endogenous causes of rare dementias causes of rare dementias (Box 2).

Endocrine and other organ failure • Neuroacanthocytosis Endocrine and other organ failure • Hypothyroidism • Cerebral lipidoses – adult variant Hypothyroidism • Hyperparathyroidism Neoplasms and paraneoplastic disorder Hypothyroidism is up to six times more com­ • Hypoparathyroidism/hypocalcaemia • Including paraneoplastic limbic mon in women than in men (Vanderpump 1995). • Diabetes mellitus encephalitis (PLE) Its clinical features include: cold, thickened • Renal encephalopathy Inflammatory/autoimmune causes skin; malar flush; coarse, brittle hair; cerebellar

• Hepatic encephalopathy • Multiple sclerosis signs; slowed reflexes; bradycardia; deafness; and carpal tunnel syndrome. Memory impairment Metabolic and other conditions • Neurosarcoidosis can progress from mild cognitive blunting • Wilson’s disease (hepatolenticular • Vasculitis to severe dementia. Depression, psychosis, degeneration) • Coeliac disease apathy, irritability and fatigue are common. • Metachromatic leukodystrophy (MLD) • Behçet disease Proximal myopathy, respiratory problems, • Adrenoleukodystrophy (ALD)/ • Systemic lupus erythematosus cardiac failure, cardiac arrhythmia and coma adrenomyeloneuropathy (AMN) • Sjögren syndrome are serious complications. Thyroid-stimulating • Neurodegeneration with brain iron hormone (TSH) levels are raised in primary accumulation type-1 (NBIA1 or hypothyroidism but are low to normal in pituitary Hallervorden–Spatz syndrome) failure. Total and free T4 thyroid levels are low,

although T3 levels may be normal. Other findings

70 Advances in psychiatric treatment (2012), vol. 18, 67–77 doi: 10.1192/apt.bp.107.004804 Gupta et al Further rare and unusual dementias

include elevated cholesterol and auto-antibodies in Renal encephalopathy Hashimoto’s thyroiditis. Electrocardiogram may Dementia due to renal failure usually has show cardiomegaly. Treatment is with thyroid potentially reversible causes. These include replacement (levothyroxine) and may reverse the uraemic encephalopathy with parathyroid cognitive impairment. hormone dys­function, dialysis dementia syndrome and dialysis-associated encephalopathy. Uraemic Hyperparathyroidism encephalopathy develops when the glomerular Primary hyperparathyroidism is caused by filtration rate declines below 10% (Alzheimer solitary adenomas (80%) or as part of multiple Europe 2009). endocrine neoplasia. The incidence of primary Neurological and cognitive symptoms in renal hyperparathyroidism is believed to be between encephalopathy can fluctuate. Early symptoms 0.01 and 0.1% (Zahrani 1997), but in people over of anorexia, nausea and restlessness progress to 60 years of age it may be as high as 0.2%, with vomiting, confusion with cognitive impairment, a prevalence of 1.0% or greater in this elderly seizures, stupor and coma. Physical signs include population (Watson 2002). The incidence peaks nystagmus, papilloedema, hyper-reflexia and between the third and fifth decades. Patients asterixis. Investigations include renal function present with recurrent renal calculi, peptic tests, creatinine clearance rates (below 15 mL/ ulcers and extensive bone resorption. Over half min), calcium, phosphate, magnesium and of those affected present with neuropsychiatric parathyroid hormone levels, and toxicology. Blood manifestations such as depression, apathy and pressure and electrocardiography (ECG) need to cognitive impairment (Geffken 1998). Some be monitored. Electroencephalography (EEG) develop psychosis, stupor and delirium. A high shows generalised slowing. level of corrected serum calcium with elevated The treatment of renal encephalopathy requires parathyroid hormone supports the diagnosis. A addressing any hypertension, diabetes, lipid prob­ technetium (99mTc) sestamibi scan can reveal an lems, acidosis and hyperkalaemia, in a specialist adenoma. Treatment is either medical or surgical. setting. Dialysis may reverse uraemic encepha­ Some of the severe neuropsychiatric manifestations lopathy. Parathyroidectomy, medical parathyroid may be reversed by parathyroidectomy. hormone suppression, erythropoietin treatment or renal transplant may also be needed. Hypoparathyroidism/hypocalcaemia Hypoparathyroidism may be idiopathic, heredi­ Hepatic encephalopathy tary or acquired. Di George syndrome is an Chronic neuropsychiatric conditions are seen autosomal-dominant form due to microdeletions of in cirrhosis, portal hypertension, fulminant chromosome 22q11.2. Smaller deletions manifest hepatic failure and following portosystemic later, primarily as parathyroid failure. Hypo­ shunt procedures (e.g. transjugular intrahepatic calcaemia is caused by hypoparathyroidism, portosystemic shunts, TIPS). This potentially chronic renal failure, vitamin D deficiency and reversible condition is caused by accumulation hypo­magnesaemia. Clinical manifestations are of toxic metabolites such as ammonia, which irritability, anxiety, psychosis, dementia, hallucin­ bypass the liver and alter brain neurotransmitter ations, depression, confusion and neuromuscular balance. Acute onset is often precipitated by irritability. Treatment involves replacement of high dietary protein intake, gastrointestinal vitamin D or calcitriol with oral calcium. haemorrhage, constipation, infection, electrolyte imbalance, shunting procedures and drugs such Diabetes mellitus as CNS depressants). Neurological signs include In patients with early-onset diabetes and those poor attention, restlessness, uncoordination and with poor glycaemic control, the presence of lethargy, which progress to delirium, stupor, micro- and macrovascular disease may cause early seizures and coma. There may be a chronic cognitive deficits. Hypertension, dyslipidaemia progressive course with cognitive blunting and and obesity are associated with diabetes and confusional states (Alzheimer Europe 2009). increase the risk of dementia. The most common Physical signs include asterixis, foetor hepaticus, impairments are in verbal memory, attention, constructional apraxia and decreased mental semantic and language functions and processing ability. Diagnosis is clinical, supported by routine speed, with relatively preserved visuospatial biochemistry. An EEG will show decreased alpha functioning (Awad 2004). Cognitive deficits are and increased delta waves. also observed in older, untreated patients but Management consists of restricting protein improve with glycaemic control. intake, correcting electrolyte imbalances and

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treating the underlying cause. Lactulose and if affected. The defect lies in the gene ABCD1. flumazenil can induce transient improvement. A There is an accumulation of very long-chain liver transplant may be needed. saturated fatty acids such as hexacosanoate in lipid-containing tissue in the brain, with Metabolic and other conditions characteristic lamellar inclusions in the Schwann Wilson’s disease cells of the CNS and the adrenal cortex. There are characteristic lamellar inclusions in the Schwann Wilson’s disease has a population prevalence of cells of the CNS and adrenal cortex, leading to 3.3/100 000. Cognitive impairment is rare and non-inflammatory axonopathy involving the ranges in severity from mild to moderate (Sternlieb spinal cord. 1990). It is an autosomal recessive disorder casued Adrenomyelo­neuropathy is the milder form, by mutations of the copper-transporting adenosine with onset at 15–30 years of age and a progressive triphosphatase (ATPase) gene on chromosome course. It affects the brain, spinal cord, adrenal 13q. There is abnormal copper deposition in the glands and testes. Clinical features include liver (causing cirrhotic changes), brain (lenticular spastic paraparesis, ataxia and sensory loss of nuclei), kidneys and corneas (Kayser–Fleischer lower limbs, language difficulties and adrenal rings), due to impaired biliary copper excretion. insufficiency. Rarely, focal signs and memory Onset usually occurs between 5 and 30 years of problems may mimic Alzheimer’s disease. age and rarely after middle age. Affect, behaviour Adrenal insufficiency progresses to Addison’s and personality abnormalities are common disease (also known as chronic or primary adrenal clinical features. Neurological features include insufficiency, hypocortisolism or hypoadrenalism). orofacial dystonia, dysarthria, dysphagia, dystonic Biochemical assay of body fluids and biopsy of postures, tremor and Parkinsonism. skin and conjunctival nerve terminals are useful Diagnosis is based on neurological and in diagnosis. Treatment is symptomatic with ophthalmological examination, ceruloplasmin adrenal hormone replacement and haematopoietic levels and liver function abnormality and is stem cell transplantation. Psychological support confirmed by liver biopsy. Brain imaging may and physiotherapy are helpful. indicate enlarged ventricles with cortical and brain- stem atrophy, in addition to T hyperintensities in 2 Neurodegeneration with brain iron accumulation the basal ganglia. type-1 (NBIA1) or Hallervorden–Spatz syndrome Treatment is with the copper-chelating agent penicillamine. There are about 100 published cases of this condition (Alzheimer Europe 2009). Familial Metachromatic leukodystrophy occurrences are more common, with autosomal Metachromatic leukodystrophy is a demyelinating recessive inheritance. There is neuroaxonal storage disease caused by deficiency of the dystrophy and iron accumulation in the basal lysosomal enzyme arylsulfatase A (ARSA). It ganglia. Common clinical features include dementia is an autosomal recessive inherited metabolic with early personality changes. Extrapyramidal disease with late juvenile and adult onset. Clinical symptoms with motor dysfunctions, gait disorder, presentation includes personality and behavioural hypotonia, rigidity, nystagmus, optic atrophy, changes, gradual loss of motor skills, optic abnormal movements and seizures may occur. atrophy, seizures, cognitive deficits and dementia Duration of illness can vary widely. A CSF analysis (Estrov 2000). Non-specific white matter lesions may show increased non-protein-bound iron. are evident on MRI. Cerebrospinal fluid proteins Electromyography (EMG) shows rigidospasticity may be increased, and ARSA enzyme activity may (fluctuating rigidity) and EEG shows generalised be decreased in leukocytes or in cultured skin slowing with spikes and sharp waves. Brain scans fibroblasts. DNA mutation analysis can be done. show generalised cortical atrophy with prominent Treatment is symptomatic and supportive. basal ganglion, brain-stem and cerebellar atrophy. Positron emission tomography (PET) shows Adrenoleukodystrophy and adreno­myelo­ hypoperfusion of the head of the caudate nucleus, neuropathy pons and cerebellum. Levodopa and dopamine This disorder affects 1/20 000 males either as agonists may provide symptomatic relief. cerebral adrenoleukodystrophy (ADL) in children or as adrenomyeloneuropathy (AMN) in adults Neuroacanthocytosis (Mosser 1993). The neonatal form is autosomal This is a group of phenotypically and genetically recessive, whereas the adult form is X-linked. hetero­geneous disorders. Neuroacanthocytosis Women are carriers and have milder presentations occurs through autosomal dominant, autosomal

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recessive or X-linked inheritance or, in sporadic cerebri (primary lymphoma of the CNS without cases, with recessive mutations in the chorein gene evidence of a mass lesion), which causes rapidly on chromosome 9 or X-linked mutation (Jarman progressing dementia. Tumours of the anterior 2002). There may be choreiform or Parkinsonian corpus callosum present with apathy, mental features, neuropathy, muscle wasting, dementia dullness and poor short-term memory. and acanthocytosis. Depression, personality Paraneoplastic disorder is a secondary effect changes and paranoia may occur. Symptoms of systemic malignancies such as squamous cell may progress slowly. At least half of patients carcinomas, before they invade, compress or meta­ develop subcortical dementia with executive and sta­sise to the nervous system. It predominantly visuospatial difficulties, and anomia in later stages. affects the grey matter and limbic system and Onset is usually in early middle age. Blood tests may be an immune-mediated disease. Para­neo­ show acanthocytes (abnormal blood cells with plastic disorder includes paraneoplastic limbic spiny protuberances) in fresh samples with normal encephalitis, focal and brain-stem encephalitis, lipid metabolism (this differentiates the disease motor neuron dysfunction (upper and lower motor from acanthocytosis in abetalipoproteinaemia – signs), subacute sensory or peripheral neuropathy, Bassen–Kornzweig syndrome). Serum creatinine cerebellar degeneration, retinopathy, autonomic kinase may be abnormal. Computed tomography dysfunction and myasthenic syndrome (Scaravilli

often shows caudate or generalised atrophy; T2- 1999). Symptoms have a subacute progression weighted MRI may show abnormal signals from which precedes diagnosis of malignancy. basal ganglia. No specific treatment exists for the Paraneoplastic limbic encephalitis leads to primary disease. Antipsychotics or tetrabenazine personality changes, irritability, memory loss may be useful for chorea. (anterograde or retrograde), seizures, altered consciousness and focal deficits. Brain-stem Cerebral lipidoses – adult variant involvement causes diplopia, gaze abnormalities, Cerebral lipidoses are a group of lysosomal facial numbness, dysarthria and dysphagia. storage diseases, with X-linked or autosomal Cerebellar symptoms include problems with recessive transmission. Rare adult forms may balance, gait and ataxia. Underlying primary cause cognitive impairment. Tay–Sachs disease malignancy such as lung, testicular or breast (also known as hexosaminidase A deficiency) carcinomas need to be excluded. Routine blood and Sandhoff disease (Jatzkewitz–Pilz syndrome, tests may be abnormal. Testing for tumour hexosaminidase A and B deficiency) are caused markers such as anti-neuronal and anti-AChR by mutation in the HEXA or HEXB genes on antibodies, voltage-gated potassium and calcium chromosome 15. They present with progressive channel antibodies, carcinoembryonic antigen, lower limb weakness, cerebellar atrophy, cancer antigen 125 and prostate-specific antigen denervation motor neuron disease and dementia. should be considered. Computed tomography of Chronic type I (non-neuropathic) Gaucher the chest, abdomen and pelvis can aid diagnosis of disease, which rarely affects adults, can lead malignancy. Brain MRI may show temporal lobe to dementia, spastic paraplegia, seizures, abnormalities but is non-specific. Inflammatory behavioural problems and psychosis. Types C cells and negative cytology are apparent on lumbar and D Niemann–Pick disease (sphingomyelin puncture. Treatment of the underlying cancer will lipidosis, sphingomyelinase deficiency) presents not necessarily lead to improvement of symptoms. with neurological and cognitive impairment due Specific immunosuppressive therapies have been to accumulation of sphingomyelin. No established tried (Keime-Guibert 2000). treatment is available for improving cognitive impairment, although enzyme replacement (in Inflammatory/autoimmune causes Gaucher disease) and a low-cholesterol diet (in Inflammatory and autoimmune disorders affecting Niemann–Pick disease) have been tried. the CNS have various aetiologies. Some of the rare hereditable causes of cognitive impairment and Neoplasms and paraneoplastic disorder dementia are listed in Box 3. Cerebral tumours are a rare cause of dementia. The most prevalent are frontal meningiomas, Multiple sclerosis multiple metastases and temporal gliomas. Clinical Over half of people with multiple sclerosis (MS) features are related to the site of the tumour, its develop some cognitive impairment, especially extent and progress. Even less common causes in the progressive forms. The exact cause of MS include neoplastic angioendotheliosis, which is probably multifactorial, involving genetic pre­ cause subacute dementia, and lymphomatosis disposition and autoimmune and environmental

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facial palsy), delirium, seizures and peripheral Box 3 Autosomal inheritance of rare dementias neuropathy. It can occur at any age, but is most Autosomal dominant Autosomal recessive common in young adults. Women and people from certain ethnic groups are most likely to be affected • Familial Alzheimer’s disease • PLOSL (e.g. African Americans). In the rare instances that • Frontotemporal lobar degenerations • Friedreich ataxia and ataxia with vitamin E children have sarcoidosis, those less than 4 years deficiency • Spinocerebellar atrophy types 1, 2 and 3 of age may present with a distinct form, causing • Amyotrophic lateral sclerosisa • Olivopontocerebellar atrophy and Charcot– enlarged lymph nodes in the chest, skin lesions and Marie–Tooth disease • Motor neuron diseasea eye swelling or redness. Around 10% of patients • Huntington’s disease • Wilson’s disease have cognitive, psychotic and neuropsychiatric

• Amyotrophic lateral sclerosisa • Neuroacanthocytosis complications (Wirnsberger 1998). There is raised a serum angiotensin-converting enzyme (ACE), and • Motor neuron disease • Metachromatic leukodystrophy CSF examination shows raised ACE, proteins, • CADASIL • Adrenoleukodystrophy (neonates) cell count and oligoclonal bands. Multiple white • Sporadic Creutzfeldt–Jakob disease • NBIA1 (Hallervorden–Spatz syndrome) matter lesions are evident on MRI. A history of • Familial Creutzfeldt–Jakob disease X-linked sarcoidosis, chest X-ray and nerve biopsy can

• Neuroacanthocytosis • Rare ataxias confirm diagnosis.

• Di George syndrome • Neuroacanthocytosis Systemic and CNS vasculitis • Adrenoleukodystrophy (males only) Vasculitis is a systemic disorder of heterogeneous CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leuko­ origin. It commonly involves the vertebral and encephalopathy; NBIA1, neurodegeneration with brain iron accumulation type-1; PLOSL, polycystic basilar arteries (posterior circulation) and may lead lipomembranous osteodysplasia with sclerosing leukoencephalo­ ­pathy. a. Some familial clustering with dominant traits of variable penetrance that rarely occurs with to cerebellar and cerebral infarction. The cause recessive traits. can be primary, for example giant cell arteritis or Takayasu’s arteritis (inflammation of the aorta); secondary, for example rheumatoid disease or infections (hepatitis B, HIV); or iatrogenic, from factors. Multiple sclerosis is a multifocal drugs such as sulfonamides. demyelinating disorder usually characterised by Vasculitis may present with fever, night periods of relapse and remission, although it can sweats and MS-like symptoms with a relapsing– have a progressive pattern. It is more common in remitting course. Severe headaches are common. women than in men. Depression is common, with Optic neuropathy, mood problems, personality raised suicide risk. Psychosis is uncommon in MS changes and multifocal/focal neurological deficits and is distinct from schizophrenia as it has a later or rapidly progressive dementia may occur. age at onset, quicker resolution, fewer relapses, Serological markers such as antineutrophil cyto­ better response to treatment and a better prognosis plasmic antibodies (ANCA) and erythrocyte (Jefferies 2006). Schizophreniform psychosis may sedimentation rate may be raised. The CSF may be secondary to steroid treatment. Cognitive show inflammatory cells and oligoclonal immuno­ deficits may precede other symptoms, progress globulin G (IgG) bands. Contrast angiography slowly and can be severe. The main cognitive and MRI can be helpful but is non-specific decline occurs in attention, concentration, verbal (Kuker 2007). fluency, comprehension, naming, executive func­ Immunotherapy achieves a partial response of tion­ing and memory. Magnetic resonance imaging cognitive and psychiatric features. reveals brain atrophy and ventricle enlargement. Oligoclonal bands are seen in the CSF. Coeliac disease (nontropical sprue) Treatment of underlying depression is with About 10% of people with coeliac disease experi­ selective serotonin reuptake inhibitors and/ ence CNS complications, but there are few recorded or cognitive–behavioural therapy. Donepezil cases of dementia, mostly case series (e.g. Collin therapy for memory and cognitive dysfunction 1991; William 2006). Coeliac disease is an auto­ has undergone trials with some positive results immune disease with genetic preponderance. There (Krupp 2004). may be a higher prevalence of gluten sensitivity in some genetic neurodegenerative disorders. Neurosarcoidosis Chronic immune-mediated inflammation, lympho­ This multisystemic granulomatous disease cytic infiltration or vasculitis of the CNS lead to principally affects the lungs. It can also involve irreversible neuronal, glial or axonal damage. the CNS, causing cranial nerve palsies (e.g. Gastrointestinal symptoms include weight loss,

74 Advances in psychiatric treatment (2012), vol. 18, 67–77 doi: 10.1192/apt.bp.107.004804 Gupta et al Further rare and unusual dementias

steatorrhoea and diarrhoea (malabsorption the CNS. These can be caused by autoantibodies syndrome). Neurological complications include (antiphospholipid, anti­ribosomal-P protein auto­ migraine, chorea, encephalopathy, cerebellar antibodies), cytokines and long-term side-effects of ataxia, peripheral neuropathy, symptoms similar gluco­cortico­steroids. The disease is more common to those of Guillain–Barré syndrome, epilepsy in women. Clinical features include fever, malaise, and depression. Dementia is of a frontosubcortical maculopapular rash, photosensitivity, oral ulcers type with rapid onset and progression. It may be and non-erosive arthritis. Common complications associated with macrocytic anaemia, leukocytosis include pneumonitis, pleurisy, pericarditis, endo­ and raised antigliadin/antiganglioside positive carditis and glomerulonephritis. Between 30 and

antibodies. Hyperintensities on T2-weighted 70% of patients have neuro­psychiatric symptoms MRI scans and diffuse slowing on EEG are non- such as psychosis, depression, personality changes, specific findings. Studies of gluten-free diets and anxiety, seizures, chorea, neuropathies, stroke and vitamin replacement have shown variable results. cognitive changes. Cognitive effects are usually Neurological symptoms may be difficult to subtle (Kirk 1991). stabilise but depression may respond to pyridoxine If suspected, encephalopathy should be

(vitamin B6) treatment. excluded. Investigations may reveal anaemia, leukopoenia, thrombocytopoenia, elevated ESR, Behçet disease antibodies against double-stranded DNA (anti- The aetiology of Behçet disease is unknown. It is dsDNA antibodies) and anti-neuronal antibodies a chronic, relapsing, multisystemic inflammatory (ANA). Anti-neuronal antibodies and oligoclonal disorder. Neurological complications include bands are present in more than half of patients. encephalopathy, sterile meningoencephalitis, Viral serology is negative. Proteinuria and renal cranial neuropathies, and cortical motor and casts, and raised CSF protein and cell count may be sensory deficits. Chronic, progressive involvement found. Non-specific cerebral atrophy, focal hyper­ of the CNS occurs in 10–20% of patients with intensities and widespread vasculopathy may be Behçet disease, particularly males in whom the detected on MRI. Skin biopsy can aid diagnosis. disease began at an early age. In the terminal stage Treatment includes corticosteroids with or with­ of the disease, 3–6% of patients develop dementia out immunosuppressive drugs. Lupus-inducing (Kaklamani 1998). When present, dementia is psychotropic drugs such as chlorpromazine, insidious with slow progression (Lishman 1998). carbamazepine and lithium should be avoided. The classical triad of symptoms includes (a) oral aphthous ulcerations, (b) genital ulcerations and Sjögren syndrome (c) ocular lesions (uveitis). There can be under­ This is an autoimmune disorder which targets lying vasculitis, with arthritis, thrombophlebitis, moisture-producing glands, causing mouth and erythema nodosum, acneiform nodules and papulo­ eye dryness. It is often associated with other auto­ pustular lesions. Depression, pseudobulbar palsy immune disorders, such as rheumatoid arthritis, (brain-stem involvement) and Parkinsonism may systemic lupus erythematosus and scleroderma. be present. Cerebral venous sinus thrombosis is a It occurs more commonly in women. Cognitive serious complication. Erythrocyte sedimentation impairment can occur but is rare and subtle. rate (ESR) may be raised and immunoglobulin A Investigations include the Schirmer test, eye or immunoglobulin M (but not immunoglobulin G) stain dye tests and slit lamp examination. Blood may be present in the CSF. Computed tomography testing for rheumatoid factors and antinuclear shows single- or multiple-density subcortical and antibodies is helpful. brain-stem lesions. General treatments include artificial tears, eye The acute phase of neurological involvement ointment (methylcellulose), steroids and immuno­ responds well to high-dose systemic corticosteroids, suppressive drugs (Ampelas 2001). which can be supplemented with cytotoxic agents (cyclophosphamide, chlorambucil and metho­ Conclusions trexate). In contrast, chronic progressive CNS It is important that patients presenting with disease responds poorly to treatment. In one study, dementia, particularly at a younger age than 20% of patients with chronic neurological involve­ usual, receive an appropriate work up. Often, they ment died within 7 years (Akman-Demir, 1996). are referred to psychiatric teams because of mood, psychotic or behavioural disturbances. Unless Systemic lupus erythematosus diagnosed early, these individuals are at risk of Systemic lupus erythematosus is a multisystemic losing out on treatment that could alleviate, control autoimmune disorder that has direct effects on or even reverse some of the symptoms. Early-onset

Advances in psychiatric treatment (2012), vol. 18, 67–77 doi: 10.1192/apt.bp.107.004804 75 Gupta et al

table 1 Population prevalence of rare dementias MCQ answers 1 d 2 b 3 e 4 d 5 d Prevalence unknown <1 case per 100 000 1–10 cases per 100 000 >10 cases per 100 000

Lyme disease Polycystic lipomembranous Familial Alzheimer’s disease Multiple system atrophya Folate deficiency osteodysplasia with Progressive supranuclear Frontotemporal lobar sclerosing leuko­ Vitamin B deficiency palsy degenerations 12 encephalopathy Vasculitis Corticobasal degeneration Pure hippocampal sclerosis Sporadic Creutzfeldt–Jakob Amyotrophic lateral sclerosis Primary progressive aphasia Sjögren syndrome disease Huntington’s disease Multiple sclerosis (rate Dementia pugilistica (more Iatrogenic Creutzfeldt– common in boxers) Spinocerebellar ataxiasa tends to increase with Jakob disease latitude,a with higher rates Chronic subdural New-variant Creutzfeldt– Friedreich ataxia haematoma in temperate zones and the Jakob disease CADASIL Western hemisphere (e.g. Paraneoplastic disorder Familial Creutzfeldt–Jakob Wilson’s disease Northern Europe), but there Anoxic brain injury disease Metachromatic are many exceptions to this Neurosyphilis leukodystrophy gradient) Herpes simplex virus Adrenoleukodystrophy­ encephalitis Adrenomyeloneuropathy­

CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. a. Prevalence varies depending on study: highest published prevalence used in this table.

dementia also has medico-legal implications for Clarke R, Smith D, Jobst KA, et al (1998) Folate, vitamin B12, and serum treating clinicians, who would be expected to total homocysteine levels in confirmed Alzheimer disease. Archives of Neurology 55: 1449–55. make adequate efforts to identify the under­lying Collin P, Pirttila T, Nurmikko T, et al (1991) Celiac disease, brain atrophy aetiology. and dementia. Neurology 41: 372–5. Clues to the underlying cause of a rare dementia Dobson AW, Erikson KM, Aschner M (2004) Manganese neurotoxicity. may be sparse, although a family history may point Annals of the New York Academy of Sciences 1012: 115–29. to an inherited condition (Box 3). A comprehensive Ernst A, Zibrak JD (1998) Carbon monoxide poisoning. New England clinical examination with appropriate investi­ga­ Journal of Medicine 339: 1603–8. tions will help diagnosis, and seeking a specialist Estrov Y, Scaglia F, Bodamer OA (2000) Psychiatric symptoms of inherited opinion from a physician or neurologist is highly metabolic disease. Journal of Inherited Metabolic Diseases 23: 2–6. recommended for atypical presentations. Fleminger S, Oliver DL, Lovestone S, et al (2003) Head injury as a risk Although psychiatrists might have theoretical factor for Alzheimer’s disease. The evidence 10 years on: a partial replication. Journal of Neurology, Neurosurgery & Psychiatry 74: 857–62. knowledge of rare dementias, they are unlikely to Fogelholm R, Waltimo O (1975) Epidemiology of chronic subdural encounter many cases in day-to-day practice. We haematoma. Acta Neurochirurgica 32: 247–50. hope that the overview of causes and estimated Geffken GR, Ward HE, Staab JP (1998) Psychiatric morbidity in endocrine prevalence rates (Table 1) presented in our disorders. Psychiatric Clinics of North America 21: 473–89. two articles will guide clinicians in prioritising Gupta S, Warner J (2008) Alcohol-related dementia: a 21st-century silent investigations, planning treatment and making epidemic? British Journal of Psychiatry 193: 351–3. referrals to appropriate medical colleagues. Gupta S, Fiertag O, Warner J (2009) Rare and unusual dementias. Advances in Psychiatric Treatment 15: 364–71. References Hayden KM, Norton MC, Darcey D, et al (2010) Occupational exposure Akman-Demir G, Baykan-Kurt B, Serdaroglu P, et al (1996) Seven-year to pesticides increases the risk of incident AD: the Cache County study. follow-up of neurologic involvement in Behçet syndrome. Archives of Neurology 74: 1524–30. Neurology 53: 691–4. Hulse GK, Lautenschlager NT, Tait RJ, et al (2005) Dementia associated Alzheimer Europe (2009) 2002–2003: Rare forms of dementia (Completed with alcohol and other drug use. International Psychogeriatrics 17 AE Projects) (http://www.alzheimer-europe.org/Alzheimer-Europe/Our- (suppl 1): s109–27. work/Completed-AE-projects/2002-2003-Rare-forms-of-dementia). Jarman PR, Wood NW (2002) Genetics of movement disorders and ataxia. Ampélas JF, Wattiaux MJ, Van Amerongen AP (2001) Psychiatric Journal of Neurology, Neurosurgery & Psychiatry 73 (suppl 2): 22–6. manifestations of lupus erythematosus systemic and Sjogren’s syndrome Jefferies K (2006) The neuropsychiatry of multiple sclerosis. Advances in [article in French]. L’Encéphale 27: 588–99. Psychiatric Treatment 12: 214–20. Awad N, Gagnon M, Messier C (2004) The relationship between impaired Kaklamani VG, Variopoulos G, Kaklamanis PG (1998) Behçet’s disease. glucose tolerance, type 2 diabetes, and cognitive function. Journal of Seminars in Arthritis and Rheumatism 27: 197–217. Clinical and Experimental Neuropsychology 26: 1044–80. Kamel F, Hoppin JA (2004) Association of pesticide exposure with Campbell A (2002) The potential role of aluminium in Alzheimer’s disease. neurologic dysfunction and disease. Environmental Health Perspectives Nephrology Dialysis Transplantation 17 (suppl 2): 17–20. 112: 950–8. Chisolm JJ Jr (1990) Evaluation of the potential role of chelation therapy Keime-Guibert F, Graus F, Fleury A, et al (2000) Treatment of paraneoplastic in treatment of low to moderate lead exposures. Environmental Health neurological syndromes with antineuronal antibodies (Anti-Hu, Anti- Perspectives 89: 67–74. Yo) with a combination of immunoglobulins, cyclophosphamide, and Choi IS (2002) Parkinsonism after carbon monoxide poisoning. European methylprednisolone. Journal of Neurology, Neurosurgery & Psychiatry Journal of Neurology 48: 30–3. 68: 479–82.

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MCQs 3 In patients with dementia caused by 5 In multiple sclerosis: Select the single best option for each question stem normal-pressure hydrocephalus: a 10% develop some cognitive impairment a cortical features such as aphasia, agnosia and b depression is uncommon 1 Raindrop pigmentation of the skin and apraxia are usually present c prevalence of the disorder is higher in men than trans­verse white lines on the fingernails b CT/MRI shows flattening of ventral horns in women (Mae’s lines) are seen in dementia caused c improvement of symptoms on shunting occurs d cognitive deficits may precede other symptoms by: in <10% e when cognitive deficits are present, attention, a lead poisoning d urinary incontinence and gait disturbance are verbal fluency and comprehension are usually b lithium toxicity uncommon spared. c folate deficiency e the dementia is usually subcortical with frontal d chronic arsenic ingestion lobe involvement in later stages, characterised e multiple sclerosis. by prominent memory loss and bradyphrenia.

2 Dementia, haemorrhage, Casal collar and 4 Regarding adrenoleukodystrophy (ALD) diarrhoea classically occur together in: and adrenomyeloneuropathy (AMN): a vitamin B deficiency 12 a Keiser–Fleischer rings commonly occur b niacin deficiency (pellagra) b ALD is a milder form that occurs in childhood c Wilson’s disease c the inheritance is autosomal dominant in both d coeliac disease ALD and AMN e systemic lupus erythematosus. d the disorder affects the brain, spinal cord, adrenal glands and testes e there are decreased fatty acids.

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