Dementia

‘…wasn’t dementia a fail-safe and soothing oblivion of the machine to its own decay?’

– Samuel Shem

The topic of dementia continues to be a mysterious one, often studied and shared by neurologists and psychiatrists. Dementia is a major public health concern, and it places a huge burden on families and carers, as well as on health services. We see a rising trend in both the incidence and prevalence of dementia globally. However, this could be due to a combination of better and more accessible diagnostic techniques along with increasing longevity.

Research done by the Alzheimer’s Society in 2013 showed the following:

• More than 800,000 people suffer from dementia (in the UK!)
• 1 in every 14 people above the age of 65 affected.

These staggering findings not only makes this a ‘hot topic’ for the Royal College examinations but also cost the NHS over £4 billion and social care services over £10 billion (Alzheimer’s Society, 2014).

So, let us start with defining dementia. What is dementia?

Dementia is NOT a disease. It is a syndrome with a set of symptoms which may be associated with certain diseases. Primarily, dementia involves a loss of mental functioning that is severe enough to impact a person’s life, be it their social, occupational or personal life.

The problems in dementia may include difficulties in memory, thinking, comprehension, planning, problem-solving and language, along with neuropsychiatric manifestations such as changes in mood, behaviour and personality.

Neuropathology of dementia

However, in practice, dementia is often a clinical diagnosis. However, to be 100% sure, a pathological examination of the post-mortem brain is needed. This makes the knowledge of neuropathological findings in dementia extremely important.

On suspecting dementia, a holistic approach to management and treatment is needed: a very comprehensive history (from the patient’s carers), cognitive tests, a thorough neurological examination, and various blood tests (dementia screen) to rule out any potential reversible causes of dementia such as B12 deficiency, hypothyroidism and infective causes. Imaging (either CT or MRI) should ideally be done as well. All this only provides 70-80% accuracy. Hence, a post-mortem remains the ‘gold standard’ for most dementias (Love, 2005).

You might be wondering how a post-mortem diagnosis would help our patient. Post-mortem exams are mostly helpful for epidemiological data, to rule out potential public health concerns with prion diseases and to potentially help estimate the risk for family members in case of inherited dementias.

Classification of dementia

• Degenerative / Irreversible – e.g. Alzheimer’s dementia, fronto-temporal dementia, Lewy body dementia, HIV related dementia, Down’s syndrome, prion diseases, vascular dementia, Huntington’s disease etc.…
• Non-degenerative / Reversible – B12 deficiency, vitamin B1 deficiency, subdural hematoma (Hakim’s triad: gait disturbance, dementia, urinary incontinence), head injury, substance misuse, hypothyroidism, lead toxicity, infective causes such as neurosyphilis and Lyme’s disease etc.…

Dementias can also be classified according to anatomical location

Cortical dementia

Affects the cerebral cortex (frontal, temporal and parietal lobes).

Examples – Alzheimer’s disease, Pick’s disease, Creutzfeldt-Jakob disease.

The ‘4As’ with cortical dementias:

• Amnesia (Memory loss).
• Aphasia (Fluent / Non-fluent).
• Apraxia (Inability to complete skilled, purposeful motor tasks which were previously learned. Brushing teeth, buttoning shirts, tying shoelaces, etc.…)
• Agnosia (Inability to recognise faces- prosopagnosia and objects).

Subcortical dementia

Affects areas beneath the cortex, the thalamus, basal ganglia and brainstem nuclei.

Examples of subcortical dementias: Huntington’s disease, progressive supranuclear palsy (PSP), Parkinson’s disease, Wilson’s disease and AIDS dementia complex.

Symptoms of subcortical dementia:

• Perseveration – Persistent repetition of a word or activity or bradyphrenia (slow cognition).
• Frontal executive dysfunction – The mnemonic SOAP is useful – Sequencing, organising, abstract thinking, problem solving, emotional lability, anhedonia etc….…
• Personality and mood changes.

Amnesia and aphasia tend to not be as severe as cortical dementias.

Mixed dementia

Cortical + subcortical features. These include fronto-temporal dementia and multi-infarct dementia.

Prevalence of various dementias

Alzheimer’s disease (causes more than 50% of all dementias) > vascular dementia > Lewy body dementia > frontotemporal dementia.

References

• Chan, G. (2021). Neuropathology: Part 1 – dementia. Trainees Online (TrON). Available online at: https://elearninghub.rcpsych.ac.uk/product?catalog=33_TRON_Neuropath_p1 [Accessed April 2023]
• Love, S. Neuropathological investigation of dementia: a guide for neurologists Journal of Neurology, Neurosurgery, and Psychiatry 2005;76(Supplement 5 ):v8–‐‑v14.
• Alzheimer’s Society (2014). Dementia UK report. [online] Alzheimer’s Society. Available online at: https://www.alzheimers.org.uk/about-us/policy-and-influencing/dementia-uk-report [Accessed Feb 2023]

Alzheimer’s disease

A bit of history! Dr Alois Alzheimer was a German psychiatrist (and a neuropathologist!)

In 1906, he encountered a strange clinical presentation of a woman named Auguste Deter and the autopsy findings of her brain. It wasn’t until 1995 that the details of Auguste were actually discovered! (Her notes were lost all those years).

Risk Factors

Non-modifiable risk factors include:

• Ageing.
• Caucasian ethnicity.
• Family history – 3-4 fold increase if a first-degree family member is affected.
• Apolipoprotein E4 variant – The largest known genetic risk factor in late-onset sporadic Alzheimer’s disease.

A third of Alzheimer’s disease cases are potentially attributable to modifiable risk factors.

Modifiable risk factors for Alzheimer’s disease are mostly related either to cardiovascular risk factors (diabetes, hypertension and obesity) or to lifestyle habits (e.g., smoking, less physical activity, diet, and mental and social activity).

The relationship between body weight and Alzheimer’s disease seems to be a consequence of midlife obesity, which could increase the risk of Alzheimer’s disease by 60%.

The association between smoking and Alzheimer’s disease risk has been controversial and remains unclear.

Epidemiological studies have shown that physical activity has a beneficial effect on brain health. In comparison with sedentary behaviours, individuals with high levels of physical activity have been shown to reduce their Alzheimer’s disease risk by half.

Cognitive, social and intellectual activity, jointly with higher education and occupational attainment, have been shown to decrease the risk of cognitive decline and dementia by increasing cognitive reserve, the capacity of the brain to resist the effects of neuropathological damage.

Neuropathology of Alzheimer’s disease

Gross anatomical features:

• Generalised brain atrophy.
• Focal atrophy of the medial temporal lobe.
• Dilatation of lateral ventricles (hydrocephalus ex vacuo) as a compensatory mechanism due to loss of other brain structures.

As expected, these changes occur due to a loss of neurons and neural connections. This loss also correlates to a loss of brain volume and weight.

The medial temporal lobe contains the hippocampus and the entorhinal cortex (a part of the limbic system). Damage to these areas leads to memory distortion, poor spatial navigation (getting lost in familiar and unfamiliar surroundings) and emotional dysregulation.

Image Source: Wikimedia Commons (2008). Alzheimer’s disease brain severe, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Alzheimer%27s_disease_brain_severe.jpg (Accessed on: 18 April 2023).

Histopathological features of Alzheimer’s disease

Senile plaques / Neuritic plaques	Neurofibrillary tangles
Develop before symptomatic cognitive impairment.	Develop at the same pace as cognitive decline.
Extracellular, beta amyloid globular structure along with surrounding degenerating neuronal processes.	Intracellular, formed due to the hyperphosphorylation of microtubule associated protein tau.
Poorly seen with H&E stain. Silver / Thioflavin S / Congo Red can be used.	Can be seen with H&E, easier to find with special stains such as silver or thioflavin S.
Origin of beta amyloid: Amyloid precursor protein (APP) is found on the cell membranes across the body, including the brain. It is cleaved by two enzymes: beta secretase and gamma secretase.

Other neuropathological findings in Alzheimer’s disease

• Cerebral amyloid angiopathy (CAA) – Beta amyloid deposition in the small and medium sized arteries of the brain. This makes these vessels prone to rupturing and can lead to intracranial bleeding.
• Granulovacuolar degeneration (GVD).
• Hirano bodies – Rod like structures. It can also be found in other neurodegenerative diseases such as frontotemporal degeneration and CJD. These are eosinophilic in nature.

These can be found in healthy individuals as well. However, an increased prevalence is noted in patients with Alzheimer’s disease.

Neuropathological staging of Alzheimer’s disease

• 2012 NIA-AA Criterion – Divides Alzheimer’s into pre-clinical, mild cognitive impairment, and dementia caused by Alzheimer’s.
• Braak and Braak staging system – Uses only neuropathological components to assess severity.
• CERAD Criteria (The consortium to establish a registry for Alzheimer’s disease) – Clinical + neuropathological components.

(Don’t worry; the exams do not go into a lot of details about this, so just being familiar with the names is enough – for now!)

References

• Chan, G. (2021). Neuropathology: Part 1 – dementia. Trainees Online (TrON). Available online at: https://elearninghub.rcpsych.ac.uk/product?catalog=33_TRON_Neuropath_p1 [Accessed April 2023]
• Patient.info. (n.d.). What is Alzheimer’s Disease – Symptoms & Stages. Available online at: https://patient.info/doctor/alzheimers-disease. [Accessed March 2023]

Vascular dementia

Vascular dementia is the second most common dementia in adults over the age of 65. It is usually common that vascular dementia is ‘mixed’ with a coexisting pathology such as Alzheimer’s disease.

There are many types of vascular dementia, such as haemorrhagic dementia and multi-infarct dementia. Small vessels are involved in diseases such as CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), which is the most common genetic cause for vascular dementia (autosomal dominant mutation of the notch 3 gene on chromosome 19).

There is a classical step-ladder type deterioration with vascular dementia.

NINDS-AIREN criteria for the clinical diagnosis of PROBABLE vascular dementia (VaD)

Presence of dementia – Cognitive decline from a higher level of functioning. This can be demonstrated as memory loss plus impairment in two or more different cognitive domains. This should be established by clinical examination and neuropsychological testing. Deficits should be severe enough to interfere with activities of daily living – not secondary effects of the cerebrovascular event alone.

Cerebrovascular disease – Defined by the presence of signs on neurological examination and / or by brain imaging.

A relationship between the above two disorders is inferred by:

• Onset of dementia within three months following a recognised stroke.
• An abrupt deterioration in cognitive functions.
• Fluctuating, stepwise progression of cognitive deficits.

Most vascular dementia is sporadic, but some cases display familial traits. Risk factors for vascular dementia include:

• History of stroke or transient ischaemic attack (TIA).
• Atrial fibrillation.
• Hypertension.
• Diabetes mellitus.
• Hyperlipidaemia.
• Smoking.
• Obesity.
• Coronary heart disease.
• Family history of stroke or cardiovascular disease.

Ischaemic changes include acute, sub-acute and chronic changes where the dead brain tissue is completely removed and replaced by scar tissue. This process is called gliosis.

References

• Chan, G. (2021). Neuropathology: Part 1 – dementia. Trainees Online (TrON). Available online at: https://elearninghub.rcpsych.ac.uk/product?catalog=33_TRON_Neuropath_p1 [Accessed April 2023]
• National Institute for Health and Care Excellence (2018). Overview | Dementia: Assessment, Management and Support for People Living with Dementia and Their Carers | Guidance | NICE. Available online at: https://www.nice.org.uk/guidance/ng97 [Accessed Feb 2023]

Frontotemporal dementia

Frontotemporal dementia (FTD) refers to a clinical syndrome of the following types:

• Semantic dementia (SD) – This could include a failure to recognise common objects. A patient might refer to a dog as a four-legged animal.
• Progressive non-fluent aphasia (PNFA) – Fragmented and broken speech, comprehension intact.
• Behavioural variant (bvFTD) – This is the most common type of FTD. This includes disinhibition, change in daily routines, and emotional dysregulation.

Since the frontal lobes are involved in emotions, behaviour, social intelligence and language, bvFTD would primarily affect these. The temporal lobes are involved with the comprehension of words. Hence, SD would primarily affect these.

So, what exactly is Pick’s disease?

FTD and Pick’s disease are often used interchangeably, but these are not exactly the same. Pick’s disease was described by Arnold Pick in 1892. Clinically, patients with Pick’s disease present similarly to patients with bvFTD. Pick’s disease is a tauopathy (excess tau proteins) and presents with behaviour changes following memory changes. In advanced stages, it often resembles Alzheimer’s disease closely.

An exam favourite is the classical ‘knife-blade’ atrophy of the frontal and temporal lobes, which shows the sharp delineation between atrophied and non-atrophied parts of the brain.

In histopathology, Pick’s disease has Pick bodies (cytoplasmic neuronal inclusions which have tau). These can be visualised well with a silver stain. This is also accompanied by neuronal loss, gliosis and microvacuolation.

Pick cells are DIFFERENT from Pick bodies – the former are swollen neurons with displaced nuclei.

In questions, terms like ‘ballooned neurons’ might be used.

References

• Alzheimer’s Society (2022). Alzheimer’s Society – United against dementia | Alzheimer’s Society. Available online at: https://www.alzheimers.org.uk/ [Accessed April 2023]
• Chan, G. (2021). Neuropathology: Part 1 – dementia. Trainees Online (TrON). Available online at: https://elearninghub.rcpsych.ac.uk/product?catalog=33_TRON_Neuropath_p1 [Accessed April 2023]

Lewy body dementia

These are named after the specific protein structures in this form of dementia called Lewy bodies.

Lewy body dementia (LBD) includes dementia with Lewy bodies and Parkinson’s disease dementia. If memory loss is present for more than a year before developing Parkinson’s disease, the diagnosis points towards dementia with Lewy bodies.

Symptoms of LBD include visual hallucinations, cognitive fluctuations, falls, sleep disturbance, movement disorders as seen with Parkinson’s disease, depression and an increased risk of neuroleptic side effects.

LBD primarily affects neurons of the substantia nigra in the midbrain. The special protein found in Lewy bodies is alpha-synuclein.

Antibodies to ubiquitin protease can be used to identify Lewy bodies. There is currently no correlation between the number of Lewy bodies and cognitive decline.

Lewy bodies can be present in the brainstem or cortex. In the brainstem, these are known as classical Lewy bodies and have a halo. These lewy bodies are the only histopathological lesions needed to make a pathological diagnosis of Lewy body dementia.

References 

• Chan, G. (2021). Neuropathology: Part 1 – dementia. Trainees Online (TrON). Available online at: https://elearninghub.rcpsych.ac.uk/product?catalog=33_TRON_Neuropath_p1 [Accessed April 2023]
• Love, S. (2005). Neuropathological investigation of dementia: a guide for neurologists. Journal of Neurology, Neurosurgery, and Psychiatry 2005;76(Supplement 5 ):v8–‐‑v14.

Delirium

Though not considered a ‘hot topic’ for the exam, delirium is a frequently seen condition in hospitalised patients.

The following should be considered when suspecting delirium:

1. Age >65 years.
2. Cognitive impairment (past or present), including dementia.
3. Any infectious or inflammatory process (UTI / sepsis/pneumonia).

Symptoms of delirium could include fluctuating cognitive functions such as confusion and poor attention, abnormal perception, agitation, restlessness, sleep disturbance and difficult social behaviour. Hypoactive delirium may include withdrawal, slow responses, reduced mobility and worsened concentration.

The 4AT score can be used to aid in a diagnosis. (Includes alertness, orientation, attention and acute change / fluctuating course). A score of 4 or above is suggestive of a possibility of delirium +/- cognitive impairment.

The management of delirium includes treating the underlying cause, ensuring clear and effective communication, preventing prolonged immobility, addressing pain, addressing polypharmacy, ensuring good hydration and nutrition, managing sensory impairment, and encouraging good sleep hygiene. Verbal de-escalation should be tried before pharmacological agents. If these fail, short-term haloperidol (usually for a week or less) can be given at a low dose and with slow titration.

In case of prolonged delirium, it is always important to rule out dementia and re-evaluate for other underlying causes.

	Delirium	Dementia
Onset	Acute.	Insidious (months to years), may be abrupt in stroke/trauma.
Vital signs	Typically abnormal (fever, tachycardia, tachypnoea).	Normal.
Course	Rapid and fluctuating.	Progressive.
Consciousness and alertness	Altered.	Usually clear.
Attention	Impaired.	Normal except in severe dementia.
Behaviour	Agitated, withdrawn, or depressed.	Intact early.
Reversibility	Usually reversible if the underlying cause is treated.	Irreversible.

References

• National Institute for Health and Care Excellence (2010). Overview | Delirium: prevention, diagnosis and management | Guidance | NICE. Available online at: https://www.nice.org.uk/guidance/CG103. [Accessed April 2023]

Prion Diseases

Most living cells contain RNA or DNA. However, prion has protein as an essential component.

The gene for prion protein is located on chromosome 20 (PrPc). The normal prion protein in healthy individuals is mostly expressed in the CNS. The role of PrPc is not clear, but it could potentially help in promoting neuronal growth and survival, copper binding, and regulating synapses, receptors, and circadian rhythms.

Sometimes, a conformational change in PrPc occurs, and a new protein known as PrPSc is formed. The amino acid sequence of this protein is the same as its healthy form. However, it has more beta sheets and fewer alpha helices.

These abnormal proteins are difficult to break down by the proteases, leading to excessive accumulation and, eventually, neurodegeneration.

Histopathological findings in prion disease is as follows:

• Vacuolation: vacuoles give a spongy appearance to the brain. (Thus, spongiform encephalopathy is another name for prion diseases).
• Dendritic loss.
• Generalised inflammation, gliosis and eventually brain atrophy.
• Poor synaptic neurotransmission.

Prion disease	Mechanism of pathogenesis
Sporadic Creutzfeldt-Jakob disease (sCJD).	Spontaneous conformational change of PrPc to PrPsc.
Sporadic fatal insomnia.	Spontaneous conformational change of PrPc to PrPsc.
Familial CJD.	Germline mutations in C-terminal PRNP (Codon 200).
Gertsmann-Straussler-Scheinker (GSS) syndrome.	Germline mutations in PRNP on codons 102 and 105.
Fatal familial insomnia (FFI).	Germline mutations in PRNP on codon 178.
Kuru.	Infection through cannibalism.
Variant CJD.	Transmission of bovine prions through the food chain.

Animal prion diseases such as scrapie, bovine spongiform encephalopathy, and feline spongiform encephalopathy are infective in aetiology.

Features of sporadic and familial CJD

Presenting signs in decreasing order of prevalence:

• Cognitive impairment and psychiatric changes.
• Cerebellar signs.
• Visual signs.
• Myoclonic jerks.
• Peripheral neuropathy.

Late signs:

• Dementia – This occurs in ALL patients who survive.
• Myoclonus.
• Cerebellar signs.
• Seizures.

Clinical features	Variant CJD	Typical sporadic CJD (MM1)
Mean age at death	29 years.	68 years.
Median duration of illness	14 months, affective and psychiatric presentation common.	5 months, Cognitive impairment, ataxia and visual signs are more common.
Thalamic MRI high signal	Pulvinar signs seen in 90% of cases.	Caudate / putamen involvement in 60% of cases.
EEG	Typical 0%.	Typical 80%.
PrPSc detection in tonsil biopsy	Positive.	Negative.

Familial Creutzfeldt-Jakob disease

• The most common mutation in familial CJD is in the E200K-129M haplotype. The clinical presentation of this is very similar to the MM1 variant of sporadic CJD.
• Very rapid progression, with an average duration of 5 months.

Sporadic and familial fatal insomnia:

• Marked sleep disturbance.
• Sympathetic overactivity.
• Cognitive impairment.
• Ataxia.

Histopathology shows atrophy of the thalamus with mild involvement of the cortex.

Gertsmann-Straussler-Scheinker syndrome

• P102L and G131V are the most common mutations.
• GSS has a much longer course of illness, with an average duration of 5 years.
• Chronic cerebellar ataxia and pyramidal signs are prominent. Dementia develops much later in life.

Iatrogenic prion disease

• Transplanted dura mater and cadaveric growth hormone are the most common causes.
• Iatrogenic prion disease can also occur after corneal and pituitary grafts.

Investigations for prion diseases

• Post-mortem to establish a definite diagnosis.
• EEG – Periodic complexes in sporadic CJD are commonly seen. These can also be present in other dementias and encephalopathies.
• CSF analysis – Often within the normal range in sporadic CJD patients. Sometimes, proteins such as 14-3-3 can be elevated in response to neuronal injury. The 14-14-3 test is not very sensitive to variant CJD.
• MRI – Cerebral atrophy can be seen in some cases of sporadic CJD. In vCJD, the posterior thalamic abnormality called pulvinar sign is very sensitive and specific.

HIV

A decline in immune functioning due to HIV / AIDS can often result in irreversible brain damage. Neuropsychiatric symptoms such as depression, memory impairment, poor concentration and behavioural changes can be seen because of this.

These symptoms together constitute HIV associated neuropsychiatric disorder (HAND).

Before ART, 20-40% of people with HIV developed HAND.

HAND can present as the following:

• Asymptomatic neurocognitive impairment – Daily life unaffected.
• Mild neurocognitive disorder.
• HIV-associated dementia – After the widespread use of ART, this now presents as a milder form called minor cognitive motor disorder (MCMD).

Investigations to diagnose HAND:

• CSF analysis – Markers such as neopterin, chemokine MCP-1, axon neurofilament light chain protein and tau protein.
• Neuroimaging to exclude treatable conditions.

HIV Entry into the brain – Acute infection with HIV loosens the tight endothelial junctions constituting the blood brain barrier. The dysregulation of the blood brain barrier and infected monocytes might lead to HIV entry into the brain. HIV predominantly infects macrophages and microglia in the central nervous system.

Multinucleated giant cells can be seen, and these are thought to be infected monocytes.

A receptor called p75NTR may contribute to damaged synapses.

Opportunistic infections

The incidence of opportunistic infections in HIV increases greatly if CD4 counts are less than 200 cells/mm3.

The common causative agents are herpes simplex virus, cytomegalovirus, polyomavirus, toxoplasmosis, cryptococcus and candida albicans.

References

• Yakub, M., Harrison, J. (2021.). Neuropathology: Part 2 – Prions and HIV. Trainees Online (TrON). Available online at: https://elearninghub.rcpsych.ac.uk/product?catalog=05_TRON_Neuropath_p2 [Accessed April 2023]
• Ghafouri, M., Amini, S., Khalili, K., & Sawaya, B. E. (2006). HIV associated dementia: symptoms and causes. Retrovirology, 3(1), 28.

Alcohol Related Brain Damage

Wernicke-Korsakoff syndrome is a favourite for paper A.

Alcohol use disorder is often associated with a thiamine deficiency. Over time, this can lead to Wernicke’s encephalopathy, where the following features are seen:

A – Ataxia.

G – Global confusion.

O – Ophthalmoplegia.

Wernicke’s encephalopathy can occur in other conditions such as dietary deficiencies, prolonged vomiting, eating disorders, etc as well. Thiamine (vitamin B1 deficiency) leads to damage to the thalamus and hypothalamus, which causes the various symptoms listed above.

It is crucial to start thiamine as soon as possible, as inappropriate treatment may lead to Korsakoff syndrome, which is composed of amnesia, disorientation, and confabulation. The mortality rates also average at about 20% if treatment is delayed. Korsakoff’s syndrome damages the neurons and supporting cells of the nervous system. The overall incidence of Korsakoff’s syndrome has considerably declined, possibly due to better nutrition.

Confabulation, in essence, is an attempt of the brain to create false memories in an attempt to fill in gaps in memory.

References

• NICE CKS. (n.d) Alcohol-problem drinking- Complications. Available online at: https://cks.nice.org.uk/topics/alcohol-problem-drinking/background-information/complications/#:~:text=Alcohol%20-%20problem%20drinking%3A%20What%20are%20the%20complications%3F [Accessed March 2023]

‌Wilson’s Disease

Although a rare disorder, this seems to be a hot topic for the exam.

Wilson’s disease is a disorder of copper metabolism due to mutations in the ATP7B gene (chromosome 13).

The function of this gene is mainly to move copper across intracellular membranes. This also helps in the production of ceruloplasmin, the copper carrier of the body. The absence of this gene in Wilson’s disease leads to a build up of copper in the liver and low copper in the rest of the body, leading to hepatic injury. Wilson’s disease is sometimes also referred to as hepatolenticular degeneration.

Inheritance – Autosomal recessive.

Ethnic variations – Slavic type shows a late age of onset and neurological features, whereas the juvenile type occurs in Western Europeans and has an age of onset before the age of 16 years. Predominantly hepatic involvement.

Age of onset – Second and third decades. Neuropsychiatric manifestation is common in young adults.

Neuropsychiatric features (commonly asked in the exam)

• Severe depression or various neurotic behavioural patterns.
• Asymmetric tremor – An early neurological sign is seen in nearly half the patients. This can either be a resting, postural or kinetic tremor.
• Dysarthria.
• Ataxia.
• Hypersalivation.
• Mask like facies.
• Pseudobulbar palsy and gait disturbance.

Parkinson’s disease is often a close differential.

Other systemic features

• Hepatic – Acute liver failure, cirrhosis, and fulminant hepatic failure.
• Ocular – Kayser-Fleischer ring – Seen in up to 95% of those with symptomatic disease. A golden-brown ring on the cornea. Although mostly associated with Wilson’s disease, this can also be seen with other hepatic conditions. Sunflower cataracts, optic neuritis and optic disc pallor may be seen.
• Renal – Fanconi’s syndrome may occur with hypercalciuria and nephrocalcinosis.
• Rheumatological – Osteopenia, chondrocalcinosis and chondromalacia patellae.
• Cardiomyopathy.
• Infertility.
• Pancreatitis.

Findings

• KF rings and low serum ceruloplasmin sufficient to make a diagnosis of Wilson’s disease.
• Elevated 24-hour urinary copper excretion.
• Genetic testing is limited.
• Assay by the enzymatic method is accurate.
• Diagnostic test – Liver biopsy.
• MRI scan – Increased density in the basal ganglia – ‘Face of the giant panda’ sign.

References

• Dr Colin Tidy (2014). Wilson’s Disease. Patient.info. Available online at: https://patient.info/doctor/wilsons-disease-pro. [Accessed April 2023]