Clinical Biochemistry of Neurological diseases Flashcards
1
Q
What neuroendocrine systems are there?
A
- Serotonin: lung and gut; carcinoid tumours – urinary 5-hydroxy-indole acetic acid (5HIAA)
- Plasma Chromogranin A: present in any cell with secretory vesicles, used as a tumour marker
- Adrenaline: adrenal medulla; sympathetic
- Oxytocin and ADH: posterior pituitary – oxytocin not really measured, - serum copeptin cleavage product of ADH can be measured
- Serum Calcitonin: medullary C cells of thyroid, tumour marker
2
Q
What is 5-HIAA and what foods are rich in this?
A
- it’s a metabolite of serotonin
- Walnuts, chocolate, Tomatoes, Aubergines, Avocado, Plums Bananas, Kiwi, Pineapple- are rich in 5-HIAA precursors
3
Q
Describe the key aspects of the Hypothalamus-pituitary axis
A
4
Q
Give an overview of endocrine circadian rhythms
A
- circadian rhythms of the pituitary hormones is controlled by the supraoptic nucleus
- many cell groups show pulsatile secretions of GH and TSH
- serum cortisol conc. are higher in the morning
- this is driven by plasma ACTH (Adrenocorticotropic hormone) conc.
5
Q
Neural tube defects
- defect and causes
A
- opening in the spinal cord or brain
- genes, environment + folate deficiency, maternal T1DM, use of certain anticonvulsants
Screening:
- Maternal serum alpha-fetoprotein
- Fetal ultrasound
6
Q
give an overview of Alpha- Fetoprotein
A
- protein that is structurally similar to albumin produced the fetal liver & yolk sac
- declines in fetus with rise in serum albumin
- peaks between week 10-20 of gestation then decrease gradually
- maternal serum AFP gradually increases through pregnancy peaks between week 28-36 then slightly decreases
- Onco-fetal Ag, is a marker of new hepatocytes:
- liver regeneration
- Hepatocellular carcinoma
7
Q
What are the key points that serum AFP levels change throughout life?
A
- Embryonal and early postnatal life
- liver generation
- hepatocellular carcinoma
- Tertocarcinoma
8
Q
What is the impact of ion conc. on neurological function?
A
9
Q
What forms of Serum Calcium are there?
A
- Total serum calcium: 2.20-2.55mmol/L
- Albumin bound: 45%
- Complexed: 5%
- Ionised (active, pH dependent 7.40): 50% - 1.15-1.35mmol/L
10
Q
Explain how hyperventilation causes hypocalcaemia
A
- hyperventilation causes respiratory alkalosis as CO2 is excreted
- this results in loss of H+ ions which makes the albumin more negatively charged
- Ca2+ is then able to bind to the now -ve albumin
- this reduces the free calcium in serum
- causes nerves to spontaneously fire off and accounts for paraesthesia in hyperventilation
11
Q
What are the effects of Nitrous oxide (whippits) use?
A
- results in subacute combined degeneration of the spinal cord and peripheral neuropathy
- converts B12 from active monovalent form to an inactive bivalent form
- Active B12 is a coenzyme for methionine synthase
- important for the generation of methyl groups for DNA RNA and myelin
12
Q
Neuropathies caused by B12 deficiency
A
- B12 deficiency usually seen in older people due to macrocytic anaemia
- due to antibodies to gastric parietal cells and intrinsic factor
- intrinsic factor needed for the binding of ingested B12
- Diseases of the terminal ileum: Cohn’s disease
- Use of Nitrous Oxide (whippits)
13
Q
Meningitis
A
- Meningism causes: headache, neck stiffness and photophobia often with N&V
- Inflammation of meninges due to infection or blood
- Blood in the CSF will show up as oxyhaemoglobin on spectrophotometry
- if blood is in vivo it is metabolised to bilirubin - measured by the scan
14
Q
Explain how CSF is collected
- different sample types
A
- obtained by a spinal tap
- 1st - Whitetop universal specimen bottle for micro (10 drops)
- 2rd - White top universal specimen bottle for biochemistry (20 drops)
- 3rd - Additional white top bottle for micro to ensure cell count decreasing (10 drops)
- can be done as a blood sample for glucose, protein, bilirubin, and rarely lactate and oligoclonal bands
15
Q
TYpes of subarachnoid Haemorrhage - Stroke
A
- Ischaemic (most common - 85%)
- Haemorrhagic - 15%
- Intracerebral - 10%
- Subarachnoid haemorrhage - 5%
- Transient ischaemic attack
16
Q
Review the pathway for examining bilirubin absorbance in CSF for detection of intracranial bleed
A
17
Q
What is this an image of?
A
Berry aneurysm causing SAH
18
Q
How does the CSF present in different causes of meningitis
A
- Bacterial meningitis
- Viral meningitis
- Fungal Meningitis
- Tuberculous Meningitis
19
Q
What is Oligoclonal banding?
A
- bands of immunoglobulins that are seen when a patient’s blood serum or cerebrospinal fluid (CSF) is analyzed. They are used in the diagnosis of various neurological and blood diseases, especially in multiple sclerosis
20
Q
What is the CSF like in Alzheimer’s disease?
A
- high concentrations of a hyperphosphorylated form of tau protein
- the hyperphosphorylation of tau cause it to lose its ability to bind to the microtubules and to stimulate their assembly
- leading to neuronal damage and the increased conc. in the CSF
- there are increased amounts of neuritic plaques and neurofibrillary tangles seen in neurons and their synapses
- these plaques are amyloid-Beta depositions leading to lower conc.s of this in the CSF
21
Q
What routine laboratory investigations are done in dementia
A
- Full blood count and ESR – vasculitis, anaemia
- Calcium – hyper/hypocalcaemia
- Folate and vitamin B12
- HbA1c - diabetes
- Liver function tests – liver failure
- Sodium, potassium, creatinine – CKD, electrolyte disorders
- Thyroid function tests - hypothyroidism
- Syphilis and HIV serology
- Systemic lupus erythematosus serology
22
Q
What could indicate a CSF leak through the nose?
A
- high concs. of asialotransferrin (B-transferrin)
- this protein is gound in v. low concs of this is plasma, nasal secretions and tears
23
Q
What are the AEIOU TIPS of altered consciousness
A
- A – alcohols – ethanol, ethylene glycol etc
- E – epilepsy, electrolyte disorders, hepatic encephalopathy
- I – insulin (hypoglycaemia), inborn errors of metabolism
- O – opiates, overdose, oxygen (hypoxia)
- U – uraemia
- T – trauma (head injury), temperature (hyperthermia), toxins, tumour (brain tumour)
- I – infections – sepsis, meningitis, encephalitis
- P – poisoning, psychogenic
- S – space-occupying lesions, stroke, seizure, shock
24
Q
What is Neurone Specific Enolase?
A
- NSE is a glycolytic enzyme released following neuronal cell death
- this positively correlates with the extent of hypoxic brain injury
- should be <16ug/L
- serial measurements 24h apart after a brain injury can indicate the prognosis of the patient
25
Explain how Ionic (osmotic) factor can cause cerebral oedema
* when the solute conc. in the brain exceeds that of the plasma osmotic gradient leads to accumulation of water into the brain --\> cerebral oedema and an impaired consciousness
* the blood-brain barrier remains intact so this pressure is maintained
26
What are some causes of Ionic (osmotic) factors that lead to cerebral oedema?
* Rapid reduction of plasma glucose in treatment od diabetic ketoacidosis or hyperosmolar hyperglycaemia with insulin
* Hyponatraemia associated causes
* Excessive IV administration of hypotonic fluids
* Excessive water intake due to excess ADH secretion
* syndrome of inappropriate ADH secretion
* Ectopic ADH secretion- small cell lung carcinoma
* MDMA (ecstasy)
27
What is Encephalitis and what are it's clinical symptoms
* Inflammatory conditions of the brain parenchyma
* altered consciousness persisting longer than 24h,
* lethargy, irritability, change in personality/ behaviour
* Fever,
* Seizures or focal neurological findings attributable to the brain parenchyma
* Lumbar puncture CSF \> 5 WBC x106/L
* EEG findings suggestive of encephalitis
* Neuroimaging suggestive of encephalitis
28
Give some causes of Encephalitis
_Infection:_
* Viral - PCR
* Person-to-person eg herpes simplex, measles, mumps etc
* Animal eg ticks (tick-borne encephalitis), dog (rabies)
* Other pathogens – eg toxoplasma, amoebae
_Auto-immune:_
* Post-infectious - acute disseminated encephalomyelitis (ADEM)
* Tumour-associated - Hu, Yo, Ri, Ma, Amphiphysin, CRMP5/CV2, Tr
* LGI1 (leucine-rich glioma inactivated 1) or CASPR2 (contactin-associated protein 2) causing ‘limbic encephalitis’.
* N-methyl-D-aspartate (NMDA) receptor causing NMDAR antibody encephalitis
* Other - sarcoidosis
29
Give examples of other antibody tests used in neurological diagnosis
* **Glutamic acid decarboxylase (GAD) (anti GAD) IgG** – Stiff Person Syndrome
* **Voltage-gated Ca2+ channel (anti-VGCC) IgG** – (Lambert Eaton) Cerebellar Ataxia
* **Ganglioside GM1 (anti-GM1) IgG and IgM (combined); Ganglioside GQ1b (anti-GQ1b) IgG and IgM** – peripheral neuropathy, Miller Fisher and Guillain Barre
* **Myelin associated glycoprotein (MAG) (anti-MAG) IgM** – peripheral neuropathy
* **Serum α3 ganglionic receptor** – autonomic neuropathy
* **CSF Orexin levels** – narcolepsy with cataplexy
* **Aquaporin-4 antibodies (NMO antibodies); Myelin oligodendrocyte glycoprotein (MOG) antibodies** – neuromyelitis optica, transverse myelitis
30
Give an example of neuropathological deposition disorders
* _Amyloid deposits_ in the brain in Alzheimer’s disease
* _Alpha-synuclein in clumps inside neurons_ in Parkinson’s disease – Lewy bodies
* _Iron deposits_ - neurodegenerative and pituitary – haemochromatosis with raised serum ferritin
* _Copper_ - neurodegenerative and pituitary – Wilson’s disease – low serum caeruloplasmin
* _Calcium_ - familial brain calcification
31
Give examples of inborn errors of metabolism affecting the eye
* Cornea clouding – eg Hurler mucopolysaccharide disease, GM1 gangliosidosis
* Lens cataract – eg galactosaemia, galactokinase deficiency
* Lens subluxation – eg Marfan’s syndrome, homocystinuria
* Retina – eg retinitis pigmentosa in Refsum disease, pantothenate kinase 2 deficiency, GM1 gangliosidosis
* Optic nerve – eg Canavan leukodystrophy
* Eye muscles – eg progressive external ophthalmoplegia - mitochondrial disorder
32
What approaches can be taken to treat Inborn Errors of Metabolism (IEMs)
* Limiting intake of precursor
* Supplying missing product
* Supplying co-factors
* Reducing accumulated product
* Blocking pathway above toxic product
* Enzyme replacement
* Organ transplantation
* Chaperone molecules
* Insertion of genetic material – nuclear and mitochondrial
33
Give an example(s) of an Anxiolytic
- Diazepam
34
Give an example of an Antipsychotic drug(s)
- Chlorpromazine
- Haloperidol
- Risperidone
- Clozapine
35
Drugs used for Mania and Bipolar disorder
- Lithium
36
Give an example of Antidepressant(s)
- Amitriptyline
- Fluoxetine
37
Give an example of Analgesics
- Paracetamol
- Ibuprofen
- Codeine phosphate
- Morphine
38
Give examples of Antiepileptic drugs
- Carbamazepine
- Sodium valproate
- Phenobarbitone
- Phenytoin
39
Drugs used in Parkinosonianism
- Ropinirole
- Levodopa
- Selegiline
- Entacapone
40
Drugs for Dementia
- Donepezil
41
Give an example(s) of Anaesthetics
- Lidocaine
- Propofol
42
What drug acts as an is an opioid antagonist?
Naloxone
43
Give an example of a neuromuscular blocking drug
- Suxamethonium
44
Give an overview of the action of Phenytoin
* Used in the treatment of epilepsy
* Variable absorption from the gut
* Metabolism by cytochrome enzymes – _genetic variation_
* Largely bound to albumin in the circulation
* Free unbound phenytoin is the active form of the drug
* Target therapeutic range 10-20 mg/L (bound plus free forms)
* ‘Free’ phenytoin target range 1-2.5 mg/L
45
What is Plasma PTH?
**Parathyroid hormone ( PTH )**, also called parathormone or parathyrin, is a hormone secreted by the parathyroid glands that is important in _bone remodelling_, which is an ongoing process in which bone tissue is alternately resorbed and rebuilt over time. _PTH is secreted in response to low blood serum calcium (Ca 2+) levels_
46
Side effects of Phenytoin
* activates enzymes that inactivate Vit D leading to decreased calcium absorption
* promotes PTH secretion to enhance calcium release from bone
47
What is Risperidone and its side effects?
* It is a dopamine receptor blocker used to treat schizophrenia
* causes hyperprolactinaemia
* prolactin secretin cells in the anterior pituitary are under inhibitory secretion control by dopamine
* if DA receptors are blocked prolactin-secreting cells are no longer under inhibition --\> increase in serum prolactin (prolactin measured before starting antipsychotics)
48
What are the consequences of hyperprolactinaemia?
* Oligospermia: deficiency of sperm cells in the semen
* Galactorrhoea: Spontaneous flow of milk from the breast unassociated with breastfeeding or childbirth
* Oligorrhoea: infrequent menstrual periods regularly going for than 35 days without menstruating
49
What drugs cause Hyperprolactinaemia?
* Antipsychotics
* Antidepressants
* Antihypertensive dyrgs
* Anticonvulsants
* Prokinetic agents
* Others: estrogens, anaesthetics, cimetidine...
50
Explain the use and side effects of Lithium
* Lithium is taken by mouth, absorbed in the small bowel and excreted in the urine.
* small therapeutic window 0.4 – 1.0 mmol/L
* Toxicity:
* Acute: vomiting and diarrhoea, dizziness
* Chronic: coarse tremor, hyperreflexia, nystagmus, ataxia, altered mental state
* Hypothyroidism: reduces iodine uptake and thyroxine release
* Increased sensitivity to ADH --\> polyuria and risk of hyponatremia
* causes increased parathyroid secretion --\> tendency to hypercalcaemia
* some evidence of impaired renal function
51
How is Lithium therapy monitored?
* Measurement of serum lithium concentrations – usually every 3 months until steady state
* Renal function – U&E
* Thyroid function
* Serum calcium
52
What are some causes of drug-induced hyponatraemia?
* Increased ADH
* Antidepressants (TCA, SSRI, MAO); antipsychotic (phenothiazines, butyrophenones e.g. haloperidol); antiepileptics (carbamazepine, oxcarbazepine, valproate); opiates
* Potentiation of ADH
* Antiepileptics (carbamazepine, lamotrigine)
* Reset osmostat
* Antidepressants (venlafaxine); antieplipetics (carbamazepine)
53
# gonadtrophin part of the cell groups that release the mammalian sex hormones
Give an overview of drug-induced hypogonadism
* Opiate induced hypogonadism: affects males and females
* Stimulation of opioid receptors in the hypothalamus leading to reduced gonadotrophin secretion
* Prescribed and recreational e.g. heroin
* Hyperprolactinaemia, see drugs above.
* Antiepileptics increase SHBG (reduce free androgens) and also suppress HPA axis, again causing hypogonadism in men and women.
54
Explain Pseudocholinesterase deficiency (suxamethonium apnoea)
* **Suxamethonium** mimics the action of acetylcholine in depolarisation at the neuromuscular junction but is hydrolysed much more slowly giving it a prolonged effect - _used as a muscle relaxant for intubation during surgery_
* decreased concs. of pseudocholinesterase will lead to prolonged effect of this drug
* hence when pseudocholinesterase is deficient the patient will take a while to breathe and move on their own after surgery
* Also increased sensitivity to other drugs
* procaine (local anaesthetic)
* some pesticides
55
How can pseudocholinesterase deficiency be identified?
* taking serum samples,
* Inhibitor studies are used to determine the phenotype as this indicates the extent of the risk of apnoea
* autosomal recessive BSCHE gene (butylrylcholinesterase)
* more common in Persian Jews and Alaska Natives
* screen relative and occupation role in pesticide workers
