Diagnosis and treatment
Diagnostic work-up: overview
Radiographic investigation of the sella turcica is considered obsolete and is rarely performed. MRI of the hypophysis is the neuroradiological technique of choice for imaging patients with pituitary adenomas. MRI distinguishes normal hypophysis from hyperpla-sia, adenomas and craniopharyngiomas.
Appropriate laboratory work-up for microadeno-mas diagnosed in otherwise asymptomatic patients (incidentalomas) includes PRL and IGF-1 levels, as PRL and GH hypersecretion are relatively common and can be clinically silent. Negative results rule out prolactinoma and acromegaly, and the absence of symptoms rules out other functioning adenomas, providing reassurance and improving the quality of life of anxious patients. Midnight salivary cortisol levels, low-dose dexamethasone suppression tests or 24 h urinary cortisol levels are not a required screening test and should be performed only in patients presenting with signs of hypercortisolism, such as central obesity, skin symptoms and myopathy. Similarly, TSH and thy-roxine (T4) levels should be measured only in patients with signs of hyperthyroidism. Tere is no indication for routine assessment of FSH/LH in asymptomatic patients presenting with a small incidentaloma.
On the other hand, all patients presenting with macroadenomas should undergo a complete hormonal evaluation, as the increased intrasellar pressure and compression on the hypophyseal stalk can decrease pituitary perfusion and reduce the delivery of hypophyseal releasing hormones. Also, patients may become hyperprolactinaemic secondary to a loss of tonic inhibition of PRL secretion. Hypopituitarism is the most common feature of patients presenting with macroadenomas, and one or more anterior-pituitary deficiencies can be demonstrated in one-third of the cases. Te clinical progression of hypopituitarism caused by macroadenomas is often slow and insidious; symptoms are non-specific and can be easily overlooked, explaining the indication for broad screening. Te notable exception to the typical indolent progression of compressive hypopituitarism is the clinical syndrome diagnosed as pituitary apoplexy. Te term ‘pituitary apoplexy’ is archaic and misleading, literally meaning ‘pituitary seizure’ (from the Greek apoplexia meaning ‘being struck down’). Pituitary apoplexy is instead an acute haemorrhagic infarction of the hypophysis resulting in a sudden, life-threatening failure of the hypophyseal-hypothalamic axis, optic chiasm compression and severe visual impairment, and mid-brain compression resulting in dysautonomic disturbances, shock and unconsciousness. Te risk of acute pituitary haemorrhagic infarction (‘apoplexy’) in patients with a macroadenoma was reported recently to be as high as 9.5% over 5 years.
In summary, in all cases of newly diagnosed mac-roadenomas, GH, PRL, LH/FSH, TSH and ACTH axes should be evaluated. Also, in addition to a full neurological examination with a particular focus on oculomotor and trigeminal abnormalities, formal visual-field testing is warranted for every patient diagnosed with a macroadenoma growing in proximity to the optic chiasm, as visual defects progress slowly -usually beginning from the superior temporal fields -and can be unnoticed by the patients.
Surgical indications
All macroadenomas have a tendency to grow and cause visual disturbances and/or hypopituitarism with time. Macroadenomas also carry a significant risk of pituitary infarction (pituitary apoplexy), and surgical hypophy-sectomy is indicated even for non-secreting, clinically silent macroadenomas, especially if the patient is young. Te same considerations apply to other non-adenomatous tumours (such as craniopharyngiomas) that are growing or exerting mass effects.
Although medical treatment can help control symptoms in all hormonally active adenomas, medical therapy is considered to be a first-choice treatment only for prolactinomas, where dopamine agonists not only control symptoms but also normalize PRL and cause shrinking of the adenoma in >90% of patients. In all other cases of hormonally active adenomas, surgery is the only curative treatment, and the vast majority of cases are candidates for transsphenoidal hypophysec-tomy. As noted above, non-radical surgical treatment can be associated with stereotactic radiotherapy in order to spare healthy hypophysis and reduce complications in selected cases.
Surgical technique
Tfie extracranial approach to the hypophysis was first described by Schloffer in 1906, who reported the excision of a pituitary tumour through the nose. Te sub-labial transseptal and transantral approaches to the hypophysis are nowadays adopted only in small children and for the excision of extremely large tumours, where the endonasal approach provides inadequate exposure of the mass. Te majority of pituitary tumours, including those with suprasellar extension, are approached transnasally with the help a magnified endoscope. Direct transnasal transphenoidal endoscopic-assisted pituitary surgery allows adequate excision of most pituitary masses, including those with suprasellar extension, and is associated with minimal cosmetic, dental and nasal complications. Te endoscopic transsphenoidal approach is also associated with a shorter period of hospitalization and with a lower incidence of hypopituitarism and diabetes insipidus (DI).
A lumbar intrathecal catheter can be used to improve intraoperative visualization of pituitary tumours in selected cases with suprasellar extension. Injection of normal saline or Hartmann’s solution in the lumbar subarachnoid space through the lumbar catheter increases CSF pressure, producing a pressure gradient that can dislocate the tumour towards the surgical field, facilitating surgery. A three-way stopcock connected to a pressure transducer can be used to monitor lumbar CSF pressure intraoperatively during CSF-volume manipulation. Particular care in lumbar catheterization should be taken in patients with large tumours or signs of raised ICP, as inadvertent CSF withdrawal at the time of lumbar drain insertion poses a risk of downward brain herniation.
The patient is positioned supine on the operating table, with a 30° head-up tilt. Local anaesthetic with vasoconstrictor is instilled into each nostril to improve surgical conditions and to minimize hypertensive responses to surgical stimulation, and the tumour is accessed through the sphenoidal air sinuses for endo-scopic excision. During excision, the anaesthetist may be required to inject saline in the lumbar catheter to improve visualization of the tumour.
After successful resection of the tumour, a Valsalva manoeuvre is used to test for CSF leaks. In the case of a significant CSF leak, the neurosurgeon will seal the sella with autologous fat, usually harvested from the patient’s thigh. After completion of surgery, nasal packs are inserted to remain in place for 48-72 h post-surgery.
Complications
The most frequent complication of transsphenoidal pituitary surgery is hypopituitarism: the reported rate of anterior pituitary failure ranges from 2 to 41%, but is <20% in most published series. Te incidence of permanent DI following pituitary surgery ranges from 3 to 9%. Other reported complications include CSF leaks (0-8%), meningitis (0-3%), new neurological deficits (0-2%), post-operative haematomas (0-6%), thromboembolic events (0-4%) and wound or nasoseptal complications (0-4%). Blood loss is usually minimal, but major haemorrhage can occur if there is surgical damage of cavernous sinuses or the carotid artery. Massive haemorrhage is an unusual but potentially fatal complication of transsphenoidal surgery.
Anaesthetic management
Pre-operative anaesthetic assessment
Routine clinical examination includes a formal neurological evaluation. Signs and symptoms of raised ICP and neurological deficits should be documented. As increased retro-orbital fat deposition is present in one-third of patients with Cushing’s disease, exophthalmos should also be documented on the anaesthetic chart, and extra care in eye protection is warranted to prevent corneal abrasions.
The upper airway should be evaluated for predictors of difficult intubation, especially in acromegaly and Cushing’s disease. Awake, fibre-optic-assisted intubation is the most prudent option if difficulties with face-mask ventilation and problematical airway access through the cricothyroid membrane are anticipated. Obesity and a history of obstructive sleep apnoea should be taken into account, and arrangements for a high-dependency bed and perioperative non-invasive positive-pressure ventilation should be made in advance in such cases. Nasal packing should be explained pre-operatively, as the patient needs to be prepared to breathe orally after surgery and until the removal of nasal packs.
Pre-operative laboratory evaluation should include coagulation and a complete blood count to assess the presence of clotting abnormalities and anaemia. Electrolytes, creatinine, urea and glycaemia should be assessed for pre-operative hyponatraemia (DI), hypo-kalaemia, renal failure and diabetes. Women presenting with amenorrhoea should have a pregnancy test before elective surgery. Patients with hypopituitarism should receive hormone replacement therapy with hydrocortisone and/or thyroxine, as guided by laboratory studies and discussed with the endocrinologist. Transsphenoidal hypophysectomy poses a minor surgical stress, and most patients on maintenance gluco-corticoid therapy (usually 30-50 mg hydrocortisone daily) do not require extra perioperative steroid cover during the perioperative period. If a ^-blockade is established, it should be continued perioperatively.
Transfusions are rarely required except for large tumours with suprasellar extension and for cranio-pharyngiomas, which have a higher risk of blood loss due to meningeal adherences. he risk ofhaemorrhagic complications should be discussed pre-operatively with the surgeon. If pre-operative volume expansion is indicated, avoid hypotonic crystalloids (dextrose). here is no indication for routine prophylactic pheny-toin. Antibiotic prophylaxis is indicated.
Induction and maintenance of anaesthesia
The fundamental principles of anaesthesia for pituitary surgery are very similar to those for other supratentorial surgical procedures. In contrast to most neuro anaesthetic procedures, the anaesthetist can be required to increase ICP in order to facilitate exposure and surgical excision of the pituitary tumour. his can be done safely in patients with small adenomas and no signs of intracranial hypertension. Ventilation is manipulated to achieve mild hypercapnia, and isotonic crystalloids can be infused through a lumbar catheter to increase CSF pressure with no adverse effects. Nitrous oxide is best avoided. During surgery, air may be injected transsphenoidaly to favour surgical exposure or to improve fluoroscopic visualization of the tumour. Nitrous oxide poses the risk of an untoward expansion of the pneumoencephalic bubble.
Our anaesthetic technique of choice is target controlled infusion (TCI) total intravenous anaesthesia (TIVA). Invasive arterial blood pressure is indicated in all patients, as transsphenoidal surgery is often associated with significant episodes of hypertension. Central venous monitoring is not routinely indicated. Visual evoked potential (VEP) monitoring has been advocated in the past for surgery close to the visual pathways. However, polysynaptic cortical waveforms such as those detected by VEP monitoring are more sensitive to the effects of anaesthetic depth than to the effects of surgery, resulting in a failure of the technique to improve post-operative visual acuity. Strong evidence supporting routine use of VEP monitoring for transsphenoidal pituitary surgery is lacking.
Osteoporosis may occur in up to 50% of patients presenting with Cushing’s disease and almost 20% of patients may have pathological fractures. Positioning should therefore be particularly careful in such cases. Some degree of head-up positioning reduces venous engorgement, with venous air embolism being a theoretical risk discussed extensively elsewhere.
The mucosal surfaces of the nose are infiltrated with local anaesthetic and a vasoconstrictor such as epineph-rine solution to reduce bleeding and facilitate dissection. Epinephrine can sometimes cause hypertension, which can usually be managed by increasing the depth of anaesthesia. A total spinal anaesthetic after inadvertent local anaesthetic injection through the cribriform plate at this stage is an extremely remote risk.
A mean arterial blood pressure between 60 and 80 mmHg at the highest point of the skull maintains cerebral perfusion with minimal oozing in the surgical field. Large respiratory volumes are sometimes required to control carbon dioxide in acromegaly. Ventilation and CSF volume can be manipulated as detailed above to facilitate tumour visualization. Hypotonic fluids are best avoided. Intraoperative fluids are administered based on starvation, insensitive losses and urinary output in catheterized patients. Blood loss is usually <100 ml.
After successful excision of the tumour, a Valsalva manoeuvre is performed to detect CSF leaks. After completion of surgery in patients with obstructive sleep apnoea, the surgeon should place a nasopha-ryngeal airway before the nose is packed. Transitional analgesia is provided with morphine (50 |xg kg-1 IV), paracetamol (1 g IV) and non-steroidal antiinflammatory drugs (NSAIDs), unless contraindicated.
Post-operative management
Neurological complications are rare and the post-operative course is usually smooth. Post-operative neurological examination should be focused on worsening visual acuity, scotomas and cranial nerve palsies. Any of these findings should trigger surgical re-exploration of the hypophysis or urgent CT.
Patients should be questioned regarding rhinor-rhea or the feeling of fluid leaking down the back of their throat. Some degree of nasal discharge is common, and the suspicion of CSF leak can be confirmed by sending the fluid for a P2-transferrin assay, which is a highly sensitive and specific test for CSF.
Given the high risk of post-operative nausea and vomiting in patients undergoing transsphenoidal pituitary surgery, and the theoretical detrimental effects of vomiting on ICP, routine pharmacological prophylaxis is indicated. Dexamethasone does not interfere with post-operative serum cortisol assays and has anti-oede-mogenic properties, and is a useful anti-emetic alongside serotonin 5-hydroxtryptamine receptor (5-HTf) antagonists (ondansetron) and histamine H1 receptor antagonist (cyclizine), which may be prescribed on an ‘as required’ basis.
Post-operative headache is relatively common, and adequate analgesia is warranted for all patients. However, narcotics and benzodiazepines should be used with extreme caution, especially in patients with a history of obstructive sleep apnoea. In such patients, a nasal airways catheter inserted through the nasal packing can be very helpful, facilitating non-invasive positive-pressure ventilation if required. Post-operative hypertension is relatively common despite adequate analgesia, and may only resolve after nasal packs are removed. Traditionally, patients with Cushing’s disease were prescribed prophylactic steroids to prevent postoperative adrenal insufficiency. In current practice, steroids are withheld and cortisol levels are tested every 6 h after surgery, in order to document disease remission. Hydrocortisone should be administered only if cortisol levels are below 2 |xg dl-1 and in the presence of signs of adrenal insufficiency.
Disorders of water balance
Antidiuretic hormone (ADH), also known as arginine vasopressin (AVP) or argipressin, is a peptide hormone synthesized in the hypothalamus and stored in vesicles in the posterior pituitary, from where it is released into the systemic circulation. Physiologically, ADH is secreted in response to dehydration. Te main effect of ADH is to cause the kidneys to concentrate and reduce the volume of urine (antidiuretic effect), thus retaining free water, diluting plasma and decreasing its osmolarity.
Disturbances in osmoregulation resulting in poly-uria and abnormalities of serum sodium concentration are common and should be monitored, even after selective transsphenoidal surgery for pituitary adenomas. Te physiological control of ADH secretion can be impaired with two opposite mechanisms: insufficient ADH secretion leading to DI, and excessive ADH secretion leading to the syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Diabetes insipidus
If the ADH-synthesizing hypothalamic nuclei are damaged during surgery, the patient will lose his or her ability to secrete ADH and to retain water. Free water is subsequently lost in large volumes with urine (hypotonic polyuria), while the plasma becomes more and more concentrated (hyperosmolar hypernatraemia). Tis condition goes under the definition of DI, which literally means ‘hypotonic polyuria’. Polyuria aside, DI has nothing in common with diabetes mellitus, and glucose metabolism is normal. Te pathogenesis of DI is insufficient antidiuresis secondary to the inability of the brain to synthesise and secrete ADH (neurogenic DI). A similar clinical scenario, not relevant to peri-operative management of patients undergoing pituitary surgery, can be caused by the inability of the kidney to respond to ADH (nephrogenic DI). Nephrogenic DI can be caused by renal amyloidosis, polycystic kidney disease, lithium toxicity, etc.
Diabetes insipidus is a common – but fortunately transitory in most cases – complication of transsphe-noidal surgery. Early post-operative DI is diagnosed in >30% of patients, while persisting DI – resulting from widespread destruction of the paraventricular and supraoptic nuclei – affects approximately 1 in 20 patients. Diabetes insipidus presents on the first or second day following surgery, with sudden profuse polyuria, often in excess of 500 ml h-1. Urine is dilute (specific gravity 1.001-1.005) and hypo-osmolar (UOsm <280 mOsm l-1). If the patient is alert and has free access to water, compensatory polydipsia will limit volume contraction and hypernatraemia. However, in fragile patients with inadequate access to fluids or impaired thirst mechanisms, as in the case of most elderly patients, failure to promptly recognize and treat DI can lead to hypovolaemic shock, severe hypernatrae-mia, coma and death.
Apart from hypernatraemia (serum Na >145 mmol l-1) and rapidly increasing serum sodium concentration, indications for treatment include the inability of the patient to match urinary output with fluid intake, resulting in progressive hypovolaemia and nocturia interfering with sleep.
In the acute setting, the subcutaneous and intrana-sal routes of administration are preferred (DDAVP 1 ^g SC or IN). Although polyuria resolves quickly with negligible haemodynamic effects, electrolytes (urinary and serum), urine output and fluid balance should be monitored closely at this stage. As DI is transient in the majority of cases, often only a single dose of DDAVP is required. In the minority of patients with persistent DI, DDAVP treatment needs to be continued – often for life – and may be administered orally. he oral starting dose of DDAVP is usually 100 |xg. Parenteral DDAVP administration is used as required during the titration of oral DDAVP.
To avoid the unnecessary risk of hyponatraemia, it is of paramount importance that treatment with DDAVP is commenced only in patients with confirmed DI. Polyuria, urine gravity <1.005 and hypernatraemia should all be confirmed before administering DDAVP. Physiological polyuria is common in the perioperative period and is often secondary to generous intravenous fluid administration, but urine is concentrated (urine gravity >1.005) and hypernatraemia is uncommon. Administration of DDAVP in such cases leads to excessive antidiuresis, inappropriate free-water retention and hyponatraemia.
Syndrome of inappropriate anti-diuretic hormone secretion
Physiologically, ADH secretion is finely tuned by hypothalamic and periventricular osmoreceptors. Following pituitary surgery, such delicate regulatory mechanisms are often impaired, and delayed inappropriate (excessive) secretion of ADH is observed in up to 25% of cases. In SIADH, free water intake exceeds free water excretion, urine is relatively concentrated and plasma becomes progressive diluted, leading to hyponatraemia (serum Na <135 mmol l-1) and serum hypo-osmolarity (POSM <280 mOsm l-1). Despite worsening hyponatraemia, excess ADH continues stimulating reabsorption of free water and urinary sodium concentration remains high (UNa >40 mEq l-1). hus, SIADH is characterized by hyponatraemia and eu- or hypervolaemia, and should therefore be distinguished from the so-called cerebral salt-wasting syndrome (CSWS), a less-understood disease featuring hyponatraemia and dehydration (hypovolaemia) due to excessive renal sodium excretion resulting from a centrally mediated process. While aggressive fluid replacement is the cornerstone of CSWS treatment, SIADH is treated with fluid restriction. Although fluid restriction is effective in the majority of SIADH cases, in the subgroup of patients presenting with severe, symptomatic hyponatraemia (headache, nausea and vomiting, seizures, coma), hypertonic saline infusions should be considered to help correct serum sodium. he use of hypertonic solutions should be cautious and sodium correction must be slow (<1 mEq h-1) in order to prevent pontine myelinolysis.
Ventriculoperitoneal shunts and allied procedures
Hydrocephalus comprises a miscellaneous group of disorders of CSF dynamics leading to an excessive accumulation of CSF within the brain, resulting in ventricular dilation and increased ICP (Table 17.1). Prior to the introduction of techniques to bypass the normal means of draining CSF, hydrocephalus had an extremely poor prognosis. Children with congenital hydrocephalus suffered disabling neurological sequelae and rarely reached adulthood. he prognosis of hydrocephalus was greatly improved by the introduction of silicone ventricular shunts, designed by John Holter, in collaboration with Eugene Spitz, in 1956. Holter realized that the available technology was clumsy, and developed the first functional silicone shunt in order to treat his own son, Casey, who was born with spina bifida and congenital hydrocephalus in 1955.
A ventricular shunt is a system of two silicone catheters connected by means of a one-way valve. he purpose of a shunt is to divert CSF from the lateral ventricles of the brain to high-capacitance bodily cavities such as the peritoneum, cardiac atrium or pleura, where CSF can be reabsorbed. Lumbar shunts serve a similar purpose, diverting CSF from the lumbar sub-arachnoid space to the pleura or peritoneum. he main clinical difference between ventricular shunts and lumbar shunts is that lumbar shunts are contraindi-cated in ‘non-communicating’ (obstructive) forms of hydrocephalus, where cranio-caudal pressure gradients could cause downward herniation of the brain as CSF is shunted from the lumbar subarachnoid space.
Each row in the table compares and contrasts commonly used terms and concepts: hydrocephalus vs. ventriculomegaly, congenital vs. acquired hydrocephalus, non-communicating vs. communicating hydrocephalus, and hydrocephalus resulting from excessive CSF production vs. impaired CSF reabsorption.
Table 17.1 Hydrocephalus: definitions and classification
|
Hydrocephalus |
Ventriculomegaly |
|
The category comprises miscellaneous abnormalities in production, flow or reabsorption of CSF, resulting in ventricular dilatation and increased ICP. |
The term describes ventricular enlargement, which can be secondary to cerebral atrophy (ex vacuo hydrocephalus). Shunting is not indicated in such cases. |
|
Congenital hydrocephalus |
Acquired hydrocephalus |
|
Typically non-communicating. Spina bifida, myelomeningocele, stenosis of the cerebral aqueduct, Arnold-Chiari malformation, arachnoid cysts, vascular malformations. |
CNS infections, subarachnoid haemorrhage, traumatic brain injury, tumours compressing or obstructing CSF pathways. |
|
Non-communicating hydrocephalus |
Communicating hydrocephalus |
|
‘Obstructive’ hydrocephalus. CSF pathways are blocked by tumours, blood clots or malformations. Absolute contraindication to lumbar shunting. Third ventriculostomy is a surgical option. |
CSF reabsorption impaired at subarachnoid granulations (bulk flow theory) or reduced brain compliance (hydrodynamic theory). Ventricular and lumbar shunting can be indicated. |
|
Pathogenesis: excessive CSF production Choroid plexus papilloma (very rare). |
Pathogenesis: impaired CSF reabsorption Vast majority of cases. Includes communicating and non-communicating forms of hydrocephalus. |
CNS, central nervous system; CSF, cerebrospinal fluid; ICP, intracranial pressure.
Cerebrospinal fluid shunting is carried out in a wide range of age groups, ranging from neonates (congenital hydrocephalus) to adults (post-traumatic, post-haemorrhagic and post-infective hydrocephalus, and idiopathic intracranial hypertension) and the elderly (normal pressure hydrocephalus, NPH).
