The day your world is shrunken by half

This is a rather interesting case I have not personally witnessed - the inspiration of writing on this topic can be traced back to one of my tutorials back in my pre-clinical years, when I was exposed to a condition involving the compression of nerves required for seeing (vision). The optic nerves are crucial for us to be able to see. Information obtained from the receptors scattered across the retina is translated into electrical impulses, where they are carried all the way, through our lovely neurones to a part of our brain called the 'occipital lobe' for interpretation. This aligns with the general principle that sensory organs are there only for receiving basic parameters of the sensation, whereas the brain is responsible for interpreting various strands of information. In terms of vision, parameters may include colour, shape and contour - just like the basic things one learns in photography classes.

However, I'm not particularly interested in the mechanics of seeing since it entails a much longer discussion than intended. In this blog article, I focus on why the patient experiences such visual defects and what exactly has afflicted him/her. To commence, I describe the facts of the case.

Patient Factsheet

We are now seeing Paul*, a 19-year old male chef who presents with progressive headaches and visual disturbances. It is additionally noted that due to the demands in the kitchen, visual ability is very important. The patient has opted for the medical consultation due to concerns of his own health and its impact on his work. He expressed his immense worry after an incident that involved him having almost set the kitchen on fire as he poured alcohol instead of soy sauce to the wok.

(Sorry, I am craving for a Chinese right now so might have made Paul a Chinese chef- these cold, lonely winter nights are making me desperate for those roasted pork buns and chicken chow mien)

Chief Complaint(s) and Characteristics:

1. Headaches (generalised): first noticed 3 months ago, persistent and progressively worse ever since; at roughly 4/10 on the Visual Analogue Scale (scale denoting the severity of pain); pain described as tensing/straining in character; could not be relieved by analgesics or any manoeuvres; exacerbated by coughing; associated with dizziness and occasional vomiting;

2. Visual Disturbances: Bilateral, progressive worsening ever since first noticed roughly four months ago; reduction in visual field (the scope of vision)- narrowing from periphery to centre; no blurriness in vision;

3. No anaemic symptoms;

4. No constitutional symptoms (e.g. unexplained, significant weight loss, anorexia, malaise, night sweats and low-grade fever);

5. No other identifiable neurological symptoms, such as limb weakness, paraesthesia (tingling sensation), or difficulty in walking and coordination;

6. Review of Systems (here's where things get interesting):

(a) Persistent thirstiness first noticed 6 weeks ago (roughly twelve glasses of water every day - evaluated by self as marked increase);

(b) Increased Urinary Frequency first noticed 6 weeks ago (roughly 10-12 times throughout the day; patient dismissed this as a sign of increased water consumption; however, it was described as 'debilitating' and impacted his work) and Nocturia (3-4 times to the toilet every night);

(c) Noticed to have enlarged nipples and breasts (mental note: need to have this appraised in the physical examination) - suspected gynaecomastia;

(d) No other endocrine symptoms; No other urinary tract symptoms (especially: no dysuria, no haematuria, no loin pain and lower quadrant abdominal pain); No symptoms reported as pertinent to the gastrointestinal tract, or other systems.

Medical History: Diagnosed asthma at the age of 10, otherwise unremarkable; asthmatic symptoms under control. From patient's account, he stopped using inhaled salbutamol due to significant symptomatic improvement throughout the past few years;

Surgical History: 3 incidents of Head Trauma (respectively at the ages of 11, 17 and 18 years) and subsequent surgical intervention; no recorded long-term consequences or post-operational complications associated with the interventions;

Drug History: No recreational drug use (he winked at me though...), no identifiable drug allergies and no chronic medication (stopped inhaled salbutamol due to dramatic improvement in asthmatic symptoms);

Family History: Uncle died of glioblastoma multiforme, an aggressive, grade 4 brain tumour; otherwise unremarkable;

Autoimmune History: Unremarkable;

Social History: Non-drinker (alcohol), non-smoker, living with family, concerned about health and career; has worked as a chef for the past two years, shortly after finishing lower-sixth;

Infectious History: Unremarkable;

Dietary History: Cravings for salty food, although not thought to be excessive or particularly serious; otherwise unremarkable. Medical advice given as to the various consequences of excessive salt intake, such as hypertension and congestive heart failure.

Now that we've got most of the information from the patient, we proceed to physical examination. Going back to the root of the issue, the patient has headaches and visual disturbances. Although the patient says that there are no other neurological symptoms, I'm not convinced. That's why I've decided to perform the following, with the findings presented below:

Physical Examinations performed & findings:

1. Full Neurological Examination (cranial nerves, upper limbs, and lower limbs);

2. Ophthalmoscopy, in exclusion of conditions such as glaucoma which involves the increase in intra-ocular pressure;

3. Breast Examination (for the alleged gynaecomastia);

4. Abdominal Examination (since the patient presents with increased urinary frequency and thirstiness).

Findings:

(a) Breast Examination- verified gynaecomastia, where there is bilateral enlargement of the breasts, with abnormally greater diameters of the areolas. There are no overlying skin changes and no other masses or scars. The contours are smooth, resembling natural breast tissue. Moreover, the structures are non-tender and soft in consistency. There is no nipple discharge elicited. There are no axillary or cervical masses.

Figure showing (left) gynaecomastia and (right) surgical correction of the breast tissue. (Extracted from: https://corpoeestetica.com/wp-content/uploads/2016/08/ginecomastia-cirurgia-660x330.jpg)

(b) Eye Examination: Generally unremarkable;

(c) Abdominal Examination: Generally unremarkable, kidneys cannot be balloted and urinary bladder normal;

(d) Upper and Lower Limb Neurological Exams: Slight dizziness and gait unsteadiness, otherwise unremarkable.

(e) Examination of Eye-related Cranial Nerves (II, III, IV, VI): No ptosis; no proptosis; normal pupillary light and accommodation reflexes bilaterally; visual acuity - 15/6 with no previously diagnosed myopia or other accommodation disorders; normal eye movements; visual fields impacted - bitemporal hemianopia, where the central vision is spared.

Examination of the other cranial nerves reveals no abnormalities.

Both diagrams illustrating the phenomenon otherwise known as 'bitemporal hemianopia' in which the lateral halves of the bilateral visual fields are lost due to compression of the optic chiasm. The first diagram is extracted from: https://jamanetwork.com/data/journals/ophth/10139/eld90031f1.png, while the second: https://i.ytimg.com/vi/alii0GcqUnM/maxresdefault.jpg.

The optic chiasm is the point of confluence of nerve fibres contained within the optic nerves of both eyes. It is the point of decussation (i.e. crossing over) of the fibres. Compression of this point leads to the unique pattern of visual field loss.

As an anatomical note to explain the patient's condition, here's a diagram showing the pituitary gland (the Master Gland, otherwise known as the administrator of hormones and the endocrine system) and its direct anatomical relations. More paramountly, you can identify the proximity between the pituitary gland and the optic chiasm. Any lesion that arises from the pituitary gland or neighbouring structures can easily lead to the compression of the optic chiasm.

Extracted from: http://upload.medbullets.com/topic/113005/images/pituitary1.jpg. As a reminder, we call the (unlabelled) vertical connection between the hypothalamus and pituitary gland, the pituitary stalk.

Here is another diagram showing the structures surrounding the pituitary gland. However, this shows the sagittal plane and zooms out a little bit. Note the closeness between the pituitary gland (as labelled) and the meninges (not labelled), the outer coverings of the brain. This is particularly true for the meninges of the basal forebrain. Any lesion arising from the meninges can easily impinge upon the optic chiasm and the pituitary gland, leading to visual field loss, visual acuity issues and endocrine problems. This diagram is extracted from: https://openi.nlm.nih.gov/imgs/512/68/2993132/PMC2993132_umj7902-089-f1.png.

At this stage, we have the following ideas regarding what manner of beast we're dealing with:

1. It's most likely a lesion present in the region very close to the pituitary gland;

2. It can arise from the following sites (regarding neuroanatomy): (a) pituitary gland, (b) hypothalamus (rather rare, but possible), (c) Meninges (at the basal forebrain);

3. This theory is attractive because a possible lesion can exert pressure upon the brain parenchyma, therefore elevating intracranial pressure. This explains the persistent headaches. Moreover, due to the closeness of the pituitary gland, hypothalamus and optic chiasm, any lesion afflicting either is likely to afflict the others. Compression of the optic chiasm, as explored above, can lead to visual field loss (bitemporal hemianopia) and significant deterioration in visual acuity;

4. Increased intracranial pressure can also lead to vomiting;

5. Moreover, compression of the pituitary gland can lead to a multiplicity of symptoms. Gynaecomastia is likely to originate from the compression of the pituitary stalk, where there is decrease in delivery of dopamine. Prolactin-secreting cells (in the anterior pituitary), not inhibited by dopamine, goes on and on. The excessive production of prolactin leads to gynaecomastia via promoted oestrogen levels in blood.

6. Polydipsia (increased thirstiness) and polyuria (increased urinary frequency) can be traced back to the hormone ADH (anti-diuretic hormone). ADH is secreted by the posterior pituitary, for the purpose of increasing water reabsorption in the collecting duct of the nephron. A lesion may compress the posterior pituitary, leading to decreased production and release of ADH in the bloodstream. This leads to the appointed symptoms since more water is lost through urine. This is called central diabetes insipidus (as opposed to the nephrogenic type, where a problem with the kidney is found);

7. The salt cravings are interesting - originally, they are thought as a sign of decreased salt reabsorption. This can be traced back to effects of compression of the anterior pituitary. The anterior pituitary also contains cells producing ACTH. ACTH is used for stimulating the adrenal glands to produce more aldosterone (although the main mechanism remains the renin-angiotensin-aldosterone system, where high blood potassium is a strong trigger), and corticosteroids. Decreased ACTH, thus lowered stimulation of production and release of both corticosteroids and aldosterone, can lead to decreased water and sodium reabsorption. However, we mustn't jump to conclusions, since the patient also has an ADH deficiency. If water consumption is equal to or greater than water excretion, then the osmolality of blood (where blood sodium concentration is not tremendously higher than baseline) can be maintained. The salt cravings can be a result of this intricate network of processes, or simply a preference of the patient. At any rate, I have advised the patient on this subject during history-taking.

Moving on, the following investigations are performed. To cut a long story short, I'm only going to show the key findings:

Investigations Performed:

1. General Tests: Full Blood Count, C-Reactive Protein, ESR (Erythrocyte Sedimentary Rate), Liver and Renal Function Tests, U&E, Hormone Panel (including thyroid function tests), Urine Dipstick, 24-hour Urine Collection (for the measurement of cortisol levels);

2. Special Tests for Diabetes Insipidus: Water Deprivation Test (to see if it's genuinely diabetes insipidus), Desmopressin Stimulation Test (using desmopressin, a chemical that is similar to ADH, aka an analogue, to see where the problem comes from: a. the brain, or b. the kidney, c. or both); Newer techniques are also adopted, including copeptin (by-product of ADH production) measurement;

3. Imaging: CT Brain for ruling out red flags (such as intracerebral haemorrhage and stroke), followed by MRI Brain for more detailed evaluation.

Investigation Findings:

The patient is diagnosed central diabetes insipidus and has slightly low concentration of ACTH. Other hormones are within normal limits. The following scans are obtained from the patient (for purposes of simplicity, only MRI Brain scans are shown):

MRI Brain (Sagittal Section) (Sequence: T1 + Contrast) [diagram extracted from Radiopaedia]

Interpretation:

1. There is a singular, well-circumscribed lesion located over the suprasellar region; By 'suprasellar', I mean it is located above the sella turcica, also known as the cradle of the pituitary gland**;

2. The lesion extends downwards to compress upon the pituitary gland (which can be shown as the hypointense patch at the antero-basal aspect of the lesion) and the optic chiasm;

3. The lesion is (largely) homogenously hyperintense to the grey matter and cerebrospinal fluid (CSF) in the lateral ventricles.

4. Roughly (I'm plucking out a random number here, since I don't have a ruler with me) larger than 1 cm x 1 cm.

Diagnosis: Craniopharyngioma.

Supplementing the above MR image, I have extracted two additional MR images provided on the Radiopaedia website which also show craniopharyngioma.

MRI T1 Sequence (Axial Image) --> the relatively smooth contours of the lesion + singularity + isointense to grey matter + location over the midbrain + homogeneity = Papillary Craniopharyngioma with significant solid component (more likely).

MRI T2 Sequence (Axial Image) - smooth-contoured, singular lesion located above the midbrain which is of variable intensity - at the left lateral aspect, there are signs of lobulated cystic components which are isointense to CSF. The rest of the lesion is mostly hypointense to the cystic components and isointense to the grey matter. It is most likely to be the solid component. Therefore, summing up the evidence, it is more likely for it to be a papillary craniopharyngioma.

Histological specimen after post-operative biopsy of the resected lesion - confirmed papillary type craniopharyngioma (Source: Pathology Outlines).

The patient then underwent surgery - the first-line treatment. There are two ways of having it done: (1) subtotal approach plus subsequent radiotherapy, or (2) radical approach where we aim to remove as much tissue as possible. There are advantages to both modalities. The main nail-biting issues are:

a. Craniopharyngiomas are quite prone to recurrence. Therefore, if we leave part of the tissue in the first run, there is greater likelihood that it might recur in the short term, necessitating further treatment. Statistics show that the tumour is likely to recur within 3 years and the rate of recurrence overall ranges from 0 to 17 per cent., should the tumour be totally removed. For those opting for subtotal removal plus radiotherapy, the likelihood of recurrence can rise to 25 to 63 per cent.

b. The radical approach might be too aggressive and overly dependent on the competence of the surgeon. What if the surgery goes too far and damages normal brain tissue?

c. The adverse effects of radiotherapy are not to be ignored, including the higher risk of post-morbid carcinogenesis and persistent seizures (due to the formation of scar tissue; in fact, many seizures arising from the temporal lobe are due to a condition called hippocampal sclerosis).

Diagram showing the various approaches which can be opted for surgical removal of a craniopharyngioma (or indeed, any suprasellar lesion, including a meningioma). This diagram is oriented on a left/posterior to right/anterior axis. Heed that the ethmoid bone, nasal bone and nasal cartilage are all located on the right, just under the big word 'transsphenoidal'. (extracted from: https://i.pinimg.com/originals/18/1b/44/181b44665ea0c495c49dd4dc806be0d8.jpg)

I particularly like this case because it's one of the extremely rare cases that present similarly to more well-established diagnoses. Here are the top three tumours that initially popped into my head:

1. Pituitary Adenoma (a benign tumour that arises from mature pituitary tissue, which is capable of producing too many hormones);

2. Meningioma (benign tumour arising from the meninges, also very prone to recurrence);

3. Craniopharyngioma (a benign tumour which arises from the Rathke's Pouch, an embryonic structure which one day becomes the lovely anterior pituitary [posterior pituitary comes from the descent of the embryonic diencephalon], which is not the usual type of hormone synthesiser).

Pituitary adenomas are capable of leading to hormonal overdrive. The other two, however, present with hormonal deficiencies, due to the persistent compression of the functional tissue of the pituitary gland. Most, in fact. For prolactin-producing cells, they are self-run and require dopamine to stop them from overdrive. Due to the mass effect exerted by tumours numbers 2 and 3 on the pituitary stalk, dopamine cannot be transported effectively to the site. There is therefore increased production of prolactin.

Craniopharyngiomas, owing to their embryonic origins, are deemed as congenital tumours and represent < 1% of all primary tumours in the central nervous system. There is no particular gender prevalence. There are two main types of craniopharyngioma in terms of histology: (1) adamantinomatous, and (2) papillary. Adamantinomatous tumours arise mostly in childhood and feature a largely cystic component, with calcifications being very common. For the papillary subtype, they predominantly occur in adults and a homogenous, solid component is the classical presentation. Multiple small cysts may be present in papillary tumours. Calcifications are much less common here.

Unfortunate Footnote: After surgery, Paul has to quit his job after having endured a post-surgical complication. His sense of smell is virtually lost and he notices the passing of a whitish fluid through his nostrils. It has to be said that the procedure has damaged the first cranial nerve, which is responsible for the sense of smell. The whitish fluid is likely to be CSF. Otherwise, he is doing fine post-operatively.

Diagram showing the course of the first cranial nerve (aka olfactory nerve) (Extracted from: https://www.earthslab.com/anatomy/the-12-pairs-of-cranial-nerves/)

As we can see, the olfactory nerves and the olfactory tract run very close to the surgical field. Whether such structures are damaged depends on the expertise of the surgeon and whether the operating field is clear during the procedure. Moreover, it needs to be clarified that every surgical procedure comes with risks. This also depends on the approach of the surgery. Referring to the diagram on the possible techniques of resecting the tumour, if the surgeon opts for, let's say, the transcallosal approach (where the incision commences from the corpus callosum, the connection between the two cerebral hemispheres), then the loss of sense of smell is unlikely to be a problem. However, for a transsphenoidal or subfrontal approach, the surgical scalpel goes perilously close to the nerve endings. If one's not careful enough, they can be damaged and this results in Paul's symptoms.

*Although I've made this clear in the first paragraph, I think it's necessary to clarify one more time. This is written from a generic point of view - it's not a case report based on a real patient. I've never seen, personally, a patient who has experienced this disease due to its relative rareness in the community. However, I still think it should be publicised and awareness should be raised since this particular condition gives rise to symptoms that overlap with several others. It also stresses on the importance of histology. Correct identification of the exact pathology also informs better treatment options and relays more accurate statistics on prognosis to the patient.

**To draw a line of distinction between the diagnostic possibilities underlying such a radiological presentation, we often ask ourselves this question: where does this lesion come from? You can decide it through the determination of where most of the lesion lies. If it comes from below and extends superiorly, it's likely to be a pituitary adenoma. Creative students might say that it's a tumour arising from the bony cradle (sella turcica of the sphenoid bone) but I've never seen or heard of it, so I remain sceptical. I found a goofy case from PubMed so if you're interested, you can check it out:

Geetha N, Kumar A, Ramachandran K, Abraham E, and Joseph F. (1999) Osteosarcoma of the sella. Australasian Radiology 43, 517-519. https://doi.org/10.1046/j.1440-1673.1999.00719.x

For lesions extending downwards from above, craniopharyngioma is only one possibility. Others include meningioma and hypothalamic tumours.

References and Further Reading:

[1] Russell RWR, Pennybacker JB. (1961) Craniopharyngioma in the Elderly. Journal of Neurology, Neurosurgery and Psychiatry, 24(1).

[2] UCLA Health. (2012, January 11). Pre-operative Imaging - Craniopharyngioma | UCLA Pituitary Tumor Program [YouTube]. Retrieved from: https://www.youtube.com/watch?v=ya3P8fbRnVs&ab_channel=UCLAHealth

[3] Vries L, Lazar L, & Phillip M. (2003). Craniopharyngioma: Presentation and Endocrine Sequelae in 36 Children. Journal Of Pediatric Endocrinology And Metabolism, 16(5). https://doi.org/10.1515/jpem.2003.16.5.703.

[4] Mrowczynski O, Langan S, & Rizk E. (2018). Craniopharyngiomas: A systematic review and evaluation of the current intratumoral treatment landscape. Clinical Neurology And Neurosurgery, 166, 124-130. https://doi.org/10.1016/j.clineuro.2018.01.039.

[5] Yang I, Sughrue M, Rutkowski M, et al. (2010). Craniopharyngioma: a comparison of tumor control with various treatment strategies. Neurosurgical Focus, 28(4), E5. https://doi.org/10.3171/2010.1.focus09307.

[6] Asa SL, Mete O. (2019). Hypothalamic Endocrine Tumors: An Update. Journal of clinical medicine, 8(10), 1741. https://doi.org/10.3390/jcm8101741.

[7] Meijer O, de Kloet E. (2016). A Refill for the Brain Mineralocorticoid Receptor: The Benefit of Cortisol Add-On to Dexamethasone Therapy. Endocrinology, 158(3), 448-454. https://doi.org/10.1210/en.2016-1495.

[8] El Ghorayeb N, Bourdeau I, & Lacroix A. (2016). Role of ACTH and Other Hormones in the Regulation of Aldosterone Production in Primary Aldosteronism. Frontiers in endocrinology, 7, 72. https://doi.org/10.3389/fendo.2016.00072.

[9] Garrahy A, Moran C, Thompson C. (2018). Diagnosis and management of central diabetes insipidus in adults. Clinical Endocrinology, 90(1), 23-30. https://doi.org/10.1111/cen.13866.

[10] Sartoretti-Schefer S, Wichmann W, Aguzzi A, et al. (1997). MR differentiation of adamantinous and squamous-papillary craniopharyngiomas. AJNR Am J Neuroradiol. 18 (1): 77-87.

[11] Zacharia BE, Bruce SS, Goldstein H, Malone HR, Neugut AI, Bruce JN. (2012). Incidence, treatment and survival of patients with craniopharyngioma in the surveillance, epidemiology and end results program. Neuro-oncology, 14(8), 1070–1078. https://doi.org/10.1093/neuonc/nos142.

[12] Craniopharyngioma. Rare Diseases Info (NIH). (2020). Retrieved 2 December 2020, from https://rarediseases.info.nih.gov/diseases/10486/craniopharyngioma#ref_1092.