(a) (i) Describe the cerebrospinal fluid (CSF) flow from site of production to its absorption. Write a note on the mechanism of…

(a)(i) Flow and absorption of cerebrospinal fluid (5 marks)

Formation and flow. CSF (total volume about 150 mL, produced at about 500 mL/day) is secreted mainly by the choroid plexuses of the lateral, third and fourth ventricles (with a small part from the ependyma and brain interstitial fluid). From the lateral ventricles it passes through the interventricular foramina of Monro to the third ventricle, and through the cerebral aqueduct (of Sylvius) to the fourth ventricle. It leaves the fourth ventricle by the median aperture (foramen of Magendie) and the two lateral apertures (foramina of Luschka) into the subarachnoid space, where it passes through the cisterns (cisterna magna and others) around the brain and spinal cord, and a little down the central canal. It is absorbed into the venous blood of the superior sagittal sinus through the arachnoid villi and granulations.

Mechanism of absorption.

• It is a pressure-dependent bulk flow. The CSF pressure (about 10 mmHg, 130 mm of CSF) is higher than the venous sinus pressure (about 6 mmHg), and absorption occurs once the gradient exceeds about 1.5 mmHg. The rate rises in proportion to the pressure difference.
• The arachnoid villi act as one-way valves. They open when CSF pressure exceeds the venous pressure and collapse when it is lower, so blood cannot enter the subarachnoid space. The CSF crosses the villous endothelium by vesicular transport in large vacuoles (or through transient open channels).
• Minor routes include the perineural lymphatic channels along cranial nerves (olfactory) and spinal nerves, and the spinal arachnoid villi. Block of absorption causes communicating hydrocephalus.

(a)(ii) Visual loss from a left occipital haemorrhage (10 marks)

The visual pathway runs as follows, as shown in the diagram: retina → optic nerve → optic chiasma → optic tract → lateral geniculate body → optic radiation → primary visual cortex (area 17, on the banks of the calcarine sulcus of the occipital lobe).

• The right visual field falls on the left half of each retina: the temporal half of the left eye and the nasal half of the right eye. The nasal fibres from the right eye cross in the chiasma and join the uncrossed temporal fibres of the left eye, so the left optic tract, lateral geniculate body, optic radiation and cortex carry the right visual field. The left hemisphere sees the right field of both eyes.
• A haemorrhage that destroys the left visual cortex therefore removes the right half of the visual field in both eyes. The loss is right-sided and homonymous (the same side in both eyes) hemianopia. Both eyes are affected, so the patient complains of loss of vision in both eyes.
• Macular sparing: the central 5–10° of the field is spared because the occipital pole, where the macula is represented (over a very large cortical area), has a dual blood supply, from the calcarine branch of the posterior cerebral artery and from the middle cerebral artery. In posterior cerebral artery territory lesions, this collateral supply, and some bilateral representation of the macula, preserve macular vision. In this patient the haemorrhage spares the pole.

(b)(i) Glomerular filtration rate and clearance tests (10 marks)

Definition. GFR is the volume of plasma filtered by all the glomeruli of both kidneys per unit time. The normal value is about 125 mL/min (about 180 L/day; 90–120 mL/min/1.73 m² of body surface, slightly lower in women, and falling with age).

Clearance principle. The clearance of a substance is the plasma volume completely cleared of it per minute, C = U × V/P, where U is the urine concentration, V the urine flow, and P the plasma concentration. The GFR equals the clearance of a marker that meets these conditions: it is freely filtered, is not reabsorbed, secreted or metabolised by the tubule, is not bound to plasma proteins, is non-toxic and can be measured easily.

Tests.

• Inulin clearance (gold standard): inulin, a fructose polymer (molecular weight 5200), meets all conditions. It is infused intravenously to keep a steady plasma level, urine is collected over timed periods, and the clearance is about 125 mL/min. It is cumbersome and is used only for research.
• Creatinine clearance: creatinine is produced from muscle and is filtered freely, and so is the usual clinical method. Its limits: it is also secreted a little by the tubule, so it overestimates GFR by 10–20% (more in advanced disease), the plasma level depends on muscle mass, diet and drugs (cimetidine, trimethoprim), and a complete timed urine collection is needed. Formulae such as Cockcroft–Gault, MDRD or CKD-EPI estimate GFR from the serum creatinine, age, sex and weight.
• Radioisotopic methods: ⁵¹Cr-EDTA, ⁹⁹ᵐTc-DTPA and ¹²⁵I-iothalamate, from plasma disappearance curves, are accurate but need special facilities.
• Iohexol clearance: a non-ionic contrast agent, measured by plasma clearance, accurate and stable.
• Cystatin C: a small protein made by all nucleated cells at a constant rate, filtered and catabolised in the tubule. It does not depend on muscle mass or sex, and detects early reduction in GFR.
• PAH clearance measures renal plasma flow, not GFR, and urea clearance underestimates it, because some urea is reabsorbed.

(b)(ii) Polymerase chain reaction (10 marks)

PCR is an in vitro technique that amplifies a specific DNA segment exponentially, by repeated thermal cycles.

Components. The template DNA, two oligonucleotide primers (forward and reverse, about 18–25 nucleotides, flanking the target), a thermostable DNA polymerase (Taq polymerase, from Thermus aquaticus), the four deoxynucleotide triphosphates (dNTPs), Mg²⁺ and a buffer, in a thermocycler.

Steps of each cycle.

• Denaturation: about 94–95 °C for 20–60 seconds, to break the hydrogen bonds and separate the two strands.
• Annealing: about 50–65 °C (below the melting temperature of the primers) for 20–40 seconds, when each primer binds to its complementary flanking sequence.
• Extension: about 72 °C for about 1 minute per kilobase, when Taq polymerase adds dNTPs at the 3′ end of each primer and copies the template.

Each cycle doubles the target, so 25–35 cycles give about 2ⁿ copies (about 10⁹ after 30 cycles). An initial long denaturation and a final extension are usually added, and the product is visualised by agarose gel electrophoresis. A variant, RT-PCR, first converts RNA to cDNA with reverse transcriptase.

Three clinical applications.

• Diagnosis of infections: detecting Mycobacterium tuberculosis (and rifampicin resistance) in sputum, HIV viral load by RT-PCR, hepatitis B and C, and SARS-CoV-2 by RT-PCR.
• Diagnosis of genetic disease: mutations in cystic fibrosis, sickle-cell disease, thalassaemia and Duchenne muscular dystrophy, including prenatal diagnosis.
• Cancer and haematology: detection of the BCR-ABL transcript in chronic myeloid leukaemia and monitoring of minimal residual disease. Other uses are DNA fingerprinting in forensic medicine and paternity, and HLA typing.

(c)(i) Functional divisions of the cerebellum (5 marks)

• Vestibulocerebellum (flocculonodular lobe, archicerebellum): receives vestibular input and projects to the vestibular nuclei. Its role is equilibrium, control of posture and the vestibulo-ocular reflex. Its lesion gives truncal ataxia and nystagmus.
• Spinocerebellum (vermis and paravermal zone, paleocerebellum): receives proprioceptive input from the spinocerebellar tracts and projects through the fastigial and interposed nuclei to the vestibular and reticular nuclei and the red nucleus. Its role is the control of muscle tone, posture and the execution of movement of trunk and limbs, correcting errors. Its lesion gives gait ataxia and hypotonia.
• Cerebrocerebellum (lateral hemispheres, neocerebellum): receives input from the cerebral cortex through the pontine nuclei and projects through the dentate nucleus and the ventrolateral thalamus to the motor and premotor cortex. Its role is the planning, timing and coordination of skilled voluntary movement, and motor learning. Its lesion gives intention tremor, dysmetria and dysdiadochokinesia on the same side.

(c)(ii) Medial and lateral descending pathways (5 marks)

• Medial (ventromedial) pathways: the anterior corticospinal, vestibulospinal, reticulospinal and tectospinal tracts. They end on motor neurons of the medial ventral horn and control axial and proximal muscles. Their functions are posture, balance, gait, and orientation of the head and neck to stimuli.
• Lateral (dorsolateral) pathways: the lateral corticospinal (pyramidal) tract and the rubrospinal tract. They end on the lateral ventral horn, on motor neurons of the distal limb muscles. The lateral corticospinal tract, which crosses at the pyramidal decussation and has direct connections to motor neurons, controls fine, skilled, voluntary movements of the hand and fingers, and the rubrospinal tract facilitates the flexors of the distal limb.

(c)(iii) Role of oxytocin in parturition and lactation (5 marks)

Oxytocin is a nonapeptide made in the supraoptic and paraventricular nuclei of the hypothalamus and released from the posterior pituitary.

• Parturition: in late pregnancy the number of oxytocin receptors in the myometrium rises sharply under oestrogen. Stretch of the cervix and vagina by the fetus sends afferent impulses to the hypothalamus (the Ferguson reflex), which releases more oxytocin, and this causes stronger uterine contractions, in a positive-feedback loop until delivery. It also stimulates decidual prostaglandin production, and after delivery it contracts the uterus, which expels the placenta and controls postpartum bleeding.
• Lactation: suckling stimulates the nipple receptors, and the impulses reach the hypothalamus through the spinal cord, releasing oxytocin, which contracts the myoepithelial cells around the alveoli and ducts, so that milk is ejected (the milk ejection or let-down reflex). The reflex can be conditioned by the sight or cry of the infant, and stress inhibits it. Prolactin, in contrast, is responsible for milk synthesis.