Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

January 31, 2009 — The gamma knife is effective in medically intractable seizures with localized foci, according to a case series of 4 children (1)

“Stereotactic radiosurgery is a noninvasive procedure that effectively treats patients with vascular malformations and brain tumors, but its efficacy for epileptogenic foci is limited, especially in children,” write Catalina Dunoyer and colleagues from the University of Miami School of Medicine in Florida.

The 4 children, ranging in age from 4 to 17 years, had medically refractory seizures and localized seizure foci identified with ictal and interictal video-EEG. Two patients had hypothalamic hamartoma (HH), and two had neocortical epilepsy. In all cases, conventional excision was technically possible but regarded as risky and was therefore declined by the patients’ families.

After radiosurgery using a gamma knife unit with Leksell stereotactic frame, stereotactic MRI imaging, and Gamma Plan workstation, there were no significant complications.

At mean follow-up of 39.2 months, 1 patient with HH and another with a probable developmental tumor in the insular cortex were seizure-free. The other patient with HH had 90% reduction of seizures. Neurobehavioral status in both patients with HH was markedly improved after surgery. The only patient who did not improve had a widespread seizure focus involving the motor strip.

“Our findings suggest that gamma knife surgery is a potentially valuable treatment modality for children with medically intractable epilepsy due to a well-localized seizure focus that is difficult to excise by conventional techniques or for whom they are deemed unsuitable,” the authors write. “More widespread application in childhood epilepsy should be investigated in larger series.”

References

1. Epilepsy. 2002;43(3):292-300

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

January 30, 2009 — In Cushing disease, a pituitary corticotroph neoplasm causes secondary adrenal hypercortisolism. This condition has known morbidity and mortality, underscoring the need for an efficient and accurate diagnostic approach. An 11 p.m. salivary cortisol level is a modern, simple initial screening tool for the diagnosis of Cushing syndrome. Confirmation with a 24-hour urinary free cortisol test and/or a low-dose dexamethasone suppression test may subsequently be performed. Patients with repeatedly equivocal results should be reevaluated after several months or undergo a corticotropin- releasing hormone (CRH) stimulation test following low-dose dexamethasone suppression to help rule out pseudo-Cushing states. The presence of low morning serum adrenocorticotropic hormone (ACTH) levels then distinguishes primary adrenal hypercortisolism from Cushing disease and the ectopic ACTH syndrome. Patients with moderate ACTH levels can undergo CRH stimulation testing to clarify the underlying disease because those with an ACTH-independent disorder have blunted subsequent ACTH levels. Once ACTH-dependent hypercortisolemia is detected, magnetic resonance (MR) imaging of the pituitary gland can be performed to detect a pituitary neoplasm. Normal or equivocal MR imaging results revealing small pituitary lesions should be followed up with inferior petrosal sinus sampling, a highly specific measure for the diagnosis of Cushing disease in experienced hands. If necessary, body imaging may be used in turn to detect sources of ectopic ACTH.

Cushing disease, first described by Harvey Cushing in 1912 in his book entitled The Pituitary Body and its Disorders, is the most common cause of spontaneous Cushing syndrome, accounting for approximately two thirds of cases.[35,36] In this disease, neoplastic corticotroph hypersecretion of ACTH leads to excessive production of cortisol from the adrenal cortex. In contrast to their normal corticotroph counterparts, the neoplastic pituitary cells in this disease are relatively resistant to negative feedback from the resultant hypercortisolism and hence continue to produce excessive ACTH, perpetuating adrenal cortisol hypersecretion. Despite the considerable prevalence of hypertension and obesity in the general population, associated temporal fossa and supraclavicular fullness are somewhat specific findings that should prompt the physician to consider screening for Cushing syndrome.[11] Other associated symptoms include, but are not limited to, bruising, myopathy, glucose intolerance, and osteoporosis. Notably, the absence of bitemporal hemianopsia is not a strong negative predictive factor for Cushing disease because the majority of patients with this disease have pituitary microadenomas.[28]

Appropriate diagnosis and management of Cushing disease is important because the mortality rate in patients with this disease is at least fourfold that in the general population matched for age and sex.[42] Control of hypercortisolism leads to gradual improvement of bruising, myopathy, central obesity, glucose intolerance and hypertension, and rapid improvement of osteoporosis.[25] Although the initial presentation of a patient with such a constellation of symptoms is suggestive of Cushing syndrome, most symptoms characteristic of the disease are nonspecific, resting the burden of an accurate diagnosis on an appropriate diagnostic workup.

• Diagnosis of Cushing Disease

Throughout the literature there are examples of imperfections and pitfalls in all available testing methods for Cushing disease. Hence, the diagnosis of Cushing disease is a rigorous process often requiring confirmatory tests at each step and endocrine consultation. A simplified diagnostic approach is delineated in Fig. 1. Beginning with a high clinical suspicion based on discriminatory physical features and/or refractory hypertension, one must initially establish a diagnosis of hypercortisolemia using an 11 p.m. salivary cortisol test. The diagnosis of Cushing syndrome is often confirmed by obtaining several salivary cortisol levels and obtaining a 24-hour UFC level or performing a low-dose dexamethasone suppression test. If these screening tests remain equivocal, the CRH stimulation test following 2 days of low-dose dexamethasone suppression can be employed to distinguish Cushing syndrome from pseudo- Cushing origins of hypercortisolemia.

Figure 1. Schematic showing a simplified diagnostic approach to Cushing disease. LDDS = low dose dexamethasone suppression; Sx = symptoms. The asterisk signifies that confirmation may be performed with 24-hour UFC or LDDS. (Click to enlarge figure)

Once true Cushing syndrome is diagnosed, it is necessary to determine the cause of the hypercortisolemia. Causes include primary adrenal hypercortisolism and secondary adrenal hypercortisolism due to either a neoplasm of pituitary corticotrophs (Cushing disease) or an ectopic neoplasm autonomously secreting ACTH. A diagnosis of primary adrenal hypercortisolism can be established by the presence of a low morning serum ACTH level. High ACTH levels suggest either the ectopic ACTH syndrome or Cushing disease. Intermediate ACTH levels should be followed by CRH stimulation testing; blunted responses in ACTH levels are diagnostic of ACTH-independent hypercortisolemia.[40]

Once ACTH-dependent hypercortisolemia is identified, MR imaging of the pituitary should be performed. Imaging findings of characteristic hypointense lesions are diagnostic of Cushing disease. Alternatively, if equivocal or negative MR imaging results are present, one should undertake inferior petrosal sinus sampling or, if the clinical suspicion is high, imaging of the neck, chest, and abdomen to search for ectopic sources of ACTH.

• Salivary Cortisol

Given that elevation of late-evening cortisol levels can be the earliest and most sensitive marker for Cushing syndrome, 12 measurement of serum or salivary cortisol levels at this time may initially prove more effective than measuring 24-hour UFC or attempting a low-dose dexamethasone suppression test. Despite the fact that midnight serum cortisol levels greater than 7.5 are highly specific (approaching 100% for patients remaining asleep) and quite sensitive (96%) for true Cushing syndrome,[38] reliably measuring serum cortisol levels at such a time is generally tedious and unrealistic, particularly given the fact that the patient should remain asleep through the test to avoid false-positive results. Promisingly, the authors of a recent study showed no significant difference between the sensitivity and specificity of midnight serum and midnight salivary cortisol levels for establishing the diagnosis of Cushing syndrome.[39] Indeed, the investigators of a larger study of 139 patients revealed a sensitivity of 93% for a set specificity of 100% for midnight salivary cortisol levels.[37] The authors of another study of 63 patients with Cushing’s syndrome reproduced the same sensitivity and specificity; furthermore, lowering the cutoff level for salivary cortisol to produce a sensitivity of 100% led to a specificity of 96%.[49] Attractively, findings of Raff et al.[41] have shown that an 11 p.m. salivary cortisol level is equal in efficacy to midnight salivary cortisol levels in terms of sensitivity and specificity for the diagnosis of Cushing syndrome.[41] Hence, a more convenient “bedtime” 11 p.m. cortisol can be measured. It is generally advisable to collect at least three late-night salivary cortisol samples on 3 different days. Indeed, equivocal results one evening may occur in the setting of pseudo-Cushing states such as depression, sleep apnea, polycystic ovarian syndrome, high physical stress, and chronic alcoholism. Interestingly, normal salivary cortisol levels are often observed on repeated testing in such patients, whereas in those with true Cushing syndrome consistently elevated salivary cortisol levels are typically found.[48] Importantly, however, physiologically elevated salivary cortisol levels during pregnancy reduce the specificity of a midnight salivary cortisol level test to 75%,[48] and salivary cortisol testing may not be readily available. In such events, 24-hour UFC and low-dose dexamethasone suppression tests are necessary in the diagnostic workup.

• Twenty-Four-Hour UFC and Low-Dose Dexamethasone Suppression

Given their imperfect sensitivity and specificity, the relatively more laborious 24-hour UFC and low-dose dexamethasone suppression tests better serve as confirmatory tests in cases of elevated late-night salivary cortisol levels or as clarifying tests in cases with equivocal levels of salivary cortisol.

Albeit tedious, a 24-hour UFC test is useful for confirming the diagnosis of Cushing syndrome. With each 24-hour UFC measurement, urine creatinine should be measured to ensure that the collections are complete; high urine volumes may raise the degree of urinary cortisol secretion.[30] The authors of some studies have shown that a 24-hour UFC level approaches a sensitivity of 100% and a population- dependent specificity of 94 to 98% in diagnosing Cushing syndrome, which is significantly superior to urinary 17-hydroxycorticosteroids (sensitivity 73% and specificity 94%).[4,29] Interestingly, one study of 30 patients with Cushing syndrome in which the investigators tested the utility of overnight (10 p.m.–8 a.m.) urinary cortisol measurements had a sensitivity of 100% and a specificity of 97%, potentially underscoring a more convenient approach.

Unfortunately, the aforementioned sensitivities and specificities are not reproducible in all studies. For example, at 100% specificity in one study, 24-hour UFC had a sensitivity of 53% for one 24-hour collection and a final sensitivity of 91% in patients with Cushing disease who underwent multiple 24-hour UFC collections.[18] The authors of another study reported a sensitivity of 45% for a specificity of 100%.[38] This study also underscored the well-known fact that pseudo-Cushing states can cause falsely elevated 24- hour UFC levels.[38]

Based on the premise that adenomatous ACTH-producing pituicytes are less likely to respond to negative feedback from steroids, low-dose dexamethasone suppression testing can serve as a confirmatory measure in the diagnosis of Cushing syndrome. Unfortunately, this approach has fallen out of favor as an initial screening test for Cushing syndrome given the difficulty in setting steroid level cutoffs that give an ample balance of sensitivity and specificity. The classic 2-day low-dose dexamethasone suppression test and overnight 1-mg low-dose dexamethasone test are likely to be falsely positive in pseudo-Cushing states and, furthermore, falsely negative in patients with mild Cushing disease because the patients may have suppressible 8 a.m. cortisol levels. The authors of a recent study employing the 2-day low-dose dexamethasone suppression test (dexamethasone 0.5 mg every 6 hours with subsequent measurement of 8 a.m. urine steroid levels) reported a 69% sensitivity and 74% specificity for this test.[50] The authors of another study showed that 18% of patients with Cushing disease had 8 a.m. cortisol values less than the typical cutoff of 5 µg/dl after an overnight 1-mg dexamethasone suppression test; furthermore, 8% had cortisol values less than 2 µg/dl.[13] Hence, like 24-hour UFC measurements, these tests are better employed as confirmatory measures than for screening alone, and, given the labor-intensive nature of a 2-day low-dose dexamethasone suppression test, it is recommended that 1-mg overnight low-dose dexamethasone suppression tests be performed.

• Corticotropin-Releasing Hormone After Low-Dose Dexamethasone Suppression

Patients in whom results are repeatedly equivocal can undergo retesting after several months or can undergo the highly specific (approaching 100%) 48-hour low-dose dexamethasone suppression with CRH stimulation test.[50] In this test, the patient receives 0.5 mg of dexamethasone every 6 hours for 2 days starting at 8 a.m. followed by CRH (1 µg/kg intravenously) on the final day at 8 a.m. Serum cortisol is then measured 15 minutes later. Although this test reinforces the low-dose dexamethasone suppression test, it crucially rules out any pseudo-Cushingoid causes of hypercortisolemia because only patients with true Cushing syndrome have sufficiently sensitive adrenal axes to have resultant serum cortisol levels greater than 1 µl.[4,14,50] Falsepositive results have been found only in heavily exercising males and patients with anorexia nervosa—two populations that would rarely come under scrutiny for a diagnosis of Cushing disease.[7,8] Despite its excellent specificity, this test is not used in all patients screened for Cushing syndrome because it is quite expensive and cumbersome.

• Serum ACTH Levels

Once the diagnosis of Cushing syndrome is established, it is necessary to determine whether the hypercortisolism is ACTH dependent or independent. This can be expeditiously established via two or three morning (8–10 a.m.) tests of serum ACTH levels.[11] It is important to keep collections on ice and promptly deliver them to the laboratory to exclude the possibility of in vitro degradation of ACTH and thus falsely low ACTH levels.

Levels less than 5 pg/ml suggest the presence of ACTHindependent hypercortisolemia, as would occur in cases of adrenal tumors or in syndromes with ectopic receptors on adrenocortical cells such as gastric inhibitory polypeptide–dependent Cushing syndrome (food-dependent Cushing syndrome) and ß-adrenergic–dependent Cushing syndrome.[22] Such patients can subsequently undergo thin section CT or MR imaging to confirm the diagnosis.

Adrenocorticotropic hormone levels greater than 20 pg/ ml suggest ACTH-dependent hypercortisolemia, as would occur in patients with Cushing disease or secondary to an ectopic ACTH-producing tumor. Of note, there is a known positive correlation between ACTH levels and adenoma size in patients with Cushing disease.[43,44] The values between 5 and 20 pg/ml, although less definitive, tend to suggest ACTH-dependent hypercortisolemia. For rigorous confirmation, patients with these intermediate levels can undergo a peripheral CRH stimulation test to distinguish ACTH-dependent from -independent Cushing syndrome, as individuals with the latter have blunted resultant ACTH levels (< 30 pg/ml).[40]

• High-Dose Dexamethasone Suppression Test

When an ACTH-dependent origin to Cushing syndrome has been established, it is finally necessary to distinguish whether the ACTH is being produced by the pituitary or an ectopic source. Statistically, the odds of having a pituitary adenoma compared with any other source is 5.5:1[35,36] However, intuitively it remains necessary to distinguish the small proportion of patients with an ectopic source of ACTH, given the neurosurgical implications of a diagnosis of the former. Interestingly, patients with the ectopic ACTH syndrome are more likely to have acute onset of symptoms, hypokalemia, and relatively higher plasma ACTH levels (mean 210 pg/ml compared with 78 pg/ml for Cushing disease).[1]

Traditionally, high-dose dexamethasone has been used to suppress pituitary sources of ACTH and hence serum cortisol levels to help distinguish Cushing disease from the ectopic ACTH syndrome. Two mg of dexamethasone is given every 6 hours for 48 hours, after which urinary cortisol is measured.[15] Suppression of basal urinary cortisol levels (measured in the initial screening) by 90% is the oftquoted cutoff for this test.[2] Unfortunately, the sensitivity of this test is limited by the fact that adequate suppression of ACTH secretion may not occur in some patients with Cushing disease. Indeed, the authors of an authoritative study of 186 patients with ACTH-dependent Cushing syndrome showed a sensitivity of 59% for this test. The sensitivity improved to 72% when the additional criterion of 64% suppression of basal urinary 17-hydroxycorticosteroid levels was added. In both cases in this study, the specificity remained 100%.[2] Despite such reports of exceptional specificity, the utility of this test has recently been challenged given the fact that many bronchial carcinoids are known to be suppressible by dexamethasone.[26,33] In a more recent study, the authors revealed a sensitivity of 81% and a specificity of 66.7% for this test, while underscoring the fact that the range of cortisol suppression was 0 to 99% for the ectopic ACTH syndrome and Cushing disease.[1] Considering these results and the aforementioned prevalence of Cushing disease in the population of patients with ACTHdependent hypercortisolemia (= 85%), the effectiveness of this test becomes dubious. Indeed, given the surgical implications of a diagnosis of Cushing disease, the decision must rest on a highly specific test. Hence, it is advised that highdose dexamethasone suppression be used more as a confirmatory test, if at all, for the diagnosis of Cushing disease.

• Imaging Detection

Because CT scanning is less sensitive than MR imaging in detecting pituitary adenomas,[16] pituitary MR imaging is a reasonable initial diagnostic step in patients with ACTHdependent hypercortisolemia. Pituitary adenomas are characteristically hypointense on T1-weighted imaging and remain so following contrast administration, which enhances the remaining normal pituitary gland and stalk. Similarly, however, pars intermedia cysts, epidermoid cysts, abscesses, infarctions, and metastases may also appear as areas of low signal intensity after the administration of contrast material.[9] A convex contour to the superior surface of the pituitary gland and/or stalk deviation, both originally thought to correlate well with the presence of an adenoma, have been shown to exist in 34 and 13% of healthy individuals, respectively.[16]

Relying on the characteristic appearance of pituitary adenomas for a radiological/neuroimaging diagnosis, pituitary MR imaging findings may be equivocal in up to half of patients with Cushing disease. Indeed, in one study, five of five patients with macroadenomas were appropriately diagnosed by MR imaging, whereas 51% of 45 patients with surgically confirmed microadenomas had positive MR imaging findings. Furthermore, in four patients the neuroimaging localization of the tumor was inaccurate.[16] Considering the fact that the authors of a recent metaanalysis of seven postmortem and three imaging studies involving pituitary adenomas reported a prevalence of 16.7% for these lesions (14.4% at postmortem and 22.5% on imaging), false-positive MR imaging results owing to underlying incidentalomas are plausible as well.[9] Indeed, the authors of a study involving 70 asymptomatic women (83% of whom were of reproductive age) and 30 asymptomatic men showed a prevalence of 10% of focal pituitary lesions in each group.[16] Furthermore, of the additional 57 patients in the study with surgically confirmed Cushing disease, six (11%) had hypointense lesions identified on MR imaging that did not correspond with the site of the actual adenoma found intraoperatively.[16] Nonetheless, in patients with ACTH-dependent hypercortisolemia, highly suggestive or relatively large (= 6 mm) pituitary lesions on MR imaging and findings more suggestive of Cushing disease—slightly elevated ACTH and cortisol levels, normal potassium levels, and insidious onset of symptoms—are essentially diagnostic of Cushing disease.

Patients in whom suggestive imaging findings are absent should undergo inferior petrosal sinus sampling to definitively confirm Cushing disease. If the suspicion is high based on signs and symptoms, patients may alternatively undergo imaging to search for ectopic ACTH-secreting neoplasms prior to inferior petrosal sampling. These patients should undergo 111In-labeled pentetreotide scanning[21,42] followed by CT and/or MR imaging of the neck, chest, and abdomen. Hyperintensity on T2-weighted MR imaging is characteristic of these neuroendocrine tumors. Importantly, however, false-positive results can occur, underscoring the need for a clinical suspicion of the ectopic ACTH syndrome prior to these tests, most often precipitated by prior negative imaging and negative inferior petrosal sinus sampling.

• Inferior Petrosal Sinus Sampling

As the venous drainage carrying pituitary-produced ACTH includes the inferior petrosal sinus, sinus sampling is an excellent method by which to distinguish Cushing disease from the ectopic ACTH syndrome. In a landmark study, Oldfield et al.[35] reported on 246 patients with surgically confirmed Cushing disease (215 cases), ectopic- ACTH syndrome (20 cases), or primary adrenal disease (11 cases), demonstrating a sensitivity and specificity of 100% for this method. It is important to underscore the fact that such sensitivities and specificities are highly operator dependent— extensive experience is an important variable.

Catheterization of each of the inferior petrosal sinuses is performed and ACTH levels in each are taken simultaneously with a peripheral level prior to and following administration of 100 µg CRH.[35] It is important to slowly aspirate venous blood over 60 seconds to help prevent retrograde venous flow. Most often, two post-CRH levels are measured— one between 2 and 3 minutes after CRH infusion and another between 5 and 6 minutes after infusion. If the ratio of either right or left inferior petrosal sinus to peripheral ACTH levels is greater than two prior to CRH stimulation or greater than three following the infusion, the test is exceedingly suggestive of Cushing disease.[35] The utility of CRH stimulation lies in the fact that ACTH secretion may be pulsatile in patients with Cushing disease,[47] requiring “unveiling” of the pulse to underscore a pituitary source of excess ACTH. Intuitively, patients with normal hypothalamic- pituitary-adrenal axes and pseudo-Cushing syndrome may have elevated petrosal sinus/peripheral ACTH ratios, particularly after CRH stimulation, underscoring the necessity of earlier testing to rule out these conditions.

Although the exceptional specificity of inferior petrosal sinus sampling for differentiating Cushing disease from ectopic ACTH syndrome has come under little scrutiny from experienced investigators, the authors of subsequent studies have revealed sensitivities of 92 to 96%.[3,20] These imperfect false-negative rates have led to attempts to further stimulate pituitary ACTH secretion by the addition of desmopressin, an ACTH secretagogue. While some ectopic ACTH-producing neoplasms are known to express V2 receptors,[45] the investigators of a recent study involving 54 patients who received CRH and desmopressin (10 µg intravenously) stimulation for inferior petrosal sinus sampling reported a sensitivity of 98% while retaining a specificity of 100% for diagnosing Cushing disease.[46] In another study, authors showed that normalizing the inferior petrosal sinus/peripheral ACTH ratio by dividing by the inferior petrosal sinus to peripheral prolactin level can improve the sensitivity of the test to 100%; all 47 patients in the study with Cushing disease had ratios greater than 0.8, whereas all patients with the ectopic ACTH syndrome had ratios less than 0.6.[10] This result underscores one likely origin of the imperfect sensitivity of inferior petrosal sinus sampling: anomalous venous drainage. Venography prior to sampling can help reveal such drainage in patients. Indeed, the authors of one study showed an improvement in the sensitivity of inferior petrosal sinus sampling (from 94 to 98%) when patients with abnormal venous drainage were excluded.[17] In another study, a ratio greater than 1.4 between inferior petrosal sinus ACTH levels correctly allowed lateralization of the lesion in 12 of 14 patients with symmetrical drainage but only four of nine patients with asymmetrical drainage (essentially no different from guessing).[27] Another group reported an accuracy of 83% in distinguishing the side of the adenoma when a difference in ACTH level greater than 1.4 between the two sinuses existed.[19] Although sampling the cavernous sinuses as an alternative to the inferior petrosal sinuses for localizing the adenoma and possibly improving diagnostic sensitivity seems intuitive, evidence has thus far shown no significant improvement compared with petrosal sinus sampling for lateralizing the lesion and diagnosing Cushing disease.[6,24]

Inferior petrosal sinus sampling is quite invasive and expensive (often $2500–5000) and thus cannot be recommended for all patients with suspected Cushing disease. Furthermore, the success of the catheterization procedure is highly operator dependent, and documented serious complications include brainstem injury (0.2%),[32] sixth nerve palsy (one in 166 patients in one study),[23] and venous thromboembolism.[34] Insertion-site hematomas occur in 3 to 4% of patients.[31,32]

Serious complications may be limited by employing internal jugular venous sampling as an alternative to inferior petrosal sinus sampling. As ACTH levels are expected to be diluted, the authors of one study used a cutoff ratio of 1.7 before CRH and 2.0 after CRH stimulation, revealing a 100% specificity and 83% sensitivity for this method in diagnosing Cushing disease.[17] The relative simplicity and safety of this approach, coupled with its exceptional specificity, make it an attractive alternative for centers less skilled at performing inferior petrosal sinus sampling.

• Conclusions

The diagnosis of Cushing disease can be efficiently confirmed by first establishing a diagnosis of Cushing syndrome via elevated 11 p.m. salivary cortisol levels. Confirmatory tests include 24-hour UFC levels and/or low-dose dexamethasone suppression tests. Patients with repeatedly equivocal results should be reevaluated after several months or undergo a CRH-stimulation test following low-dose dexamethasone suppression to help rule out pseudo-Cushing states. Low serum ACTH levels then distinguish primary adrenal hypercortisolism from Cushing disease and ectopic ACTH syndrome. A CRH stimulation test can be performed to clarify the underlying disease in patients with equivocal serum ACTH levels. Once ACTHdependent hypercortisolemia is detected, MR imaging of the pituitary can be performed to detect a pituitary neoplasm. Normal MR imaging results or those revealing noncharacteristic small pituitary lesions should be followed up with inferior petrosal sinus sampling and then imaging (111In-labeled pentetreotide scanning followed by CT and/or MR imaging of the neck, chest, and abdomen) if necessary to detect sources of ectopic ACTH. Modern modifications to the inferior petrosal sinus sampling procedure include the addition of desmopressin to CRH to further improve sensitivity of the test or alternatively measuring internal jugular ACTH levels, a far less invasive approach that retains specificity with a fall in sensitivity to 83%.[17,46]

• Abbreviation Notes

ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; CT = computed tomography; MR = magnetic resonance; UFC = urinary free cortisol. 

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6. Doppman JL, Nieman LK, Chang R, Yanovski J, Cutler GB Jr, Chrousos GP, et al: Selective venous sampling from the cavernous sinuses is not a more reliable technique than sampling from the inferior petrosal sinuses in Cushing’s syndrome. J Clin Endocrinol Metab 80:2485–2489, 1995

7. Duclos M, Corcuff JB, Pehourcq F, Tabarin A: Decreased pituitary sensitivity to glucocorticoids in endurance-trained men. Eur J Endocrinol 144:363–368, 2001

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17. Ilias I, Chang R, Pacak K, Oldfield EH, Wesley R, Doppman J, et al: Jugular venous sampling: an alternative to petrosal sinus sampling for the diagnostic evaluation of adrenocorticotropic hormone- dependent Cushing’s syndrome. J Clin Endocrinol Metab 89:3795–3800, 2004

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19. Kaltsas GA, Giannulis MG, Newell-Price JD, Dacie JE, Thakkar C, Afshar F, et al: A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing’s disease and the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 84:487–492, 1999

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32. Miller DL, Doppman JL, Peterman SB, Nieman LK, Oldfield EH, Chang R: Neurologic complications of petrosal sinus sampling. Radiology 185:143–147, 1992

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34. Obuobie K, Davies JS, Ogunko A, Scanlon MF: Venous thromboembolism following inferior petrosal sinus sampling in Cushing’s disease. J Endocrinol Invest 23:542–544, 2000

35. Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, et al: Petrosal sinus sampling with and without corti- cotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 325:897–905, 1991

36. Orth DN: Cushing’s syndrome. N Engl J Med 332:791–803, 1995

37. Papanicolaou DA, Mullen N, Kyrou I, Nieman LK: Nighttime salivary cortisol: a useful test for the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 87:4515–4521, 2002

38. Papanicolaou DA, Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK: A single midnight serum cortisol measurement distinguishes Cushing’s syndrome from pseudo-Cushing states. J Clin Endocrinol Metab 83:1163–1167, 1998

39. Putignano P, Toja P, Dubini A, Pecori Giraldi F, Corsello SM, Cavagnini F: Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing’s syndrome. J Clin Endocrinol Metab 88:4153–4157, 2003

40. Raff H, Findling JW: A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med 138:980–991, 2003

41. Raff H, Raff JL, Findling JW: Late-night salivary cortisol as a screening test for Cushing’s syndrome. J Clin Endocrinol Metab 83:2681–2686, 1998

42. Ross EJ, Linch DC: Cushing’s syndrome—killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet 2:646–649, 1982

43. Selvais P, Donckier J, Buysschaert M, Maiter D: Cushing’s disease: a comparison of pituitary corticotroph microadenomas and macroadenomas. Eur J Endocrinol 138:153–159, 1998

44. Tremble JM, Buxton-Thomas M, Hopkins D, Kane P, Bailey D, Harris PE: Cushing’s syndrome associated with a chemodectoma and a carcinoid tumor. Clin Endocrinol (Oxf) 52:789–793, 2000

45. Tsagarakis S, Tsigos C, Vasiliou V, Tsiotra P, Kaskarelis J, Sotiropoulou C, et al: The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion. J Clin Endocrinol Metab 87:1646–1653, 2002

46. Tsagarakis S, Vassiliadi D, Kaskarelis IS, Komninos J, Souvatzoglou E, Thalassinos N: The application of the combined corticotropin- releasing hormone plus desmopressin stimulation during petrosal sinus sampling is both sensitive and specific in differentiating patients with Cushing’s disease from patients with the occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab 92:2080–2086, 2007

47. van den Berg G, Frolich M, Veldhuis JD, Roelfsema F: Combined amplification of the pulsatile and basal modes of adrenocorticotropin and cortisol secretion in patients with Cushing’s disease: evidence for decreased responsiveness of the adrenal glands. J Clin Endocrinol Metab 80:3750–3757, 1995

48. Viardot A, Huber P, Puder JJ, Zulewski H, Keller U, Muller B: Reproducibility of nighttime salivary cortisol and its use in the diagnosis of hypercortisolism compared with urinary free cortisol and overnight dexamethasone suppression test. J Clin Endocrinol Metab 90:5730–5736, 2005

49. Yaneva M, Mosnier-Pudar H, Dugue MA, Grabar S, Fulla Y, Bertagna X: Midnight salivary cortisol for the initial diagnosis of Cushing’s syndrome of various causes. J Clin Endocrinol Metab 89:3345–3351, 2004

50. Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK: Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA 269: 2232–2238, 1993

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

January 30, 2009 — The treatment of patients with persistently active acromegaly has been facilitated over the past decade by the advent of highly specific and selective pharmacological agents. Somatostatin analogs, derived from the native inhibitory hormone somatostatin, are available in extended-duration preparations and are effective in reducing serum levels of growth hormone (GH) and insulin-like growth factor–I (IGF-I) as well as in improving the adverse clinical effects of acromegaly. Cabergoline, an agonist with a specificity for the dopamine D-2 receptor, has been shown to suppress IGF-I levels and induce tumor shrinkage in 35 and 50% of patients, respectively. The GH receptor antagonists compete with naturally occurring GH for binding with the GH receptor. As such, pegvisomant normalizes circulating IGF-I levels in 80 to 90% of patients with acromegaly. This last line of therapy should be considered for use in patients in whom surgery and medical therapy with somatostatin and/or dopamine agonists are either ineffective or poorly tolerated.

The last decade has provided major progress in the development of highly specific and selective pharmacological agents that have greatly facilitated a more aggressive approach to the treatment of patients with persistently active acromegaly. In this article we will summarize current evidence for each of the major classes of pharmacotherapeutic agents, with special emphasis on their recognized benefits and risks. An attempt will be made to highlight patient subpopulations for whom unique combinations of treatment options should be considered.

• Pharmacotherapeutic Agents

• Somatostatin Analogs

Derived from the native inhibitory hormone somatostatin, this class of agents represents a physiologically based approach to treating GH excess. The first-generation analogs had a halflife that lasted 2 hours longer than that of the native hormone and required subcutaneous administration at least three times a day. This class of analogs successfully reduces GH and IGF-I levels in 50 to 70% of patients and provides an IGF-I normalization rate of approximately 30% in patients in whom pituitary surgery has failed.[11] Maximal suppression of hormone is reached within 2 hours and usually lasts for 6 hours. Because the decline in the GH level is rapid, the assessment of suppression can be made at the outset to identify the patient’s potential responsiveness to octreotide. In patients in whom GH levels return to baseline before the end of the dosing interval, the frequency of administration can be further increased. Increasing the daily dose beyond 300 to 600 µg/day rarely achieves a greater effect.[9] To address some of these shortcomings, newer formulations of somatostatin analogs (octreotide-LAR and lanreotide–sustained release) with more extended durations of action have been developed. Administered in single intramuscular injections (10–40 mg every 28 days), these analogs result in similar, if not greater efficacy than that achieved with the subcutaneous formulations.[2] The effects are more sustained than those of subcutaneous preparations and, therefore, compliance is presumably enhanced. Somatostatin analog responsiveness has been correlated with the somatostatin receptor subtype in some,[18] but not all studies.[4,8] The GH inhibitory effects of octreotide are also significantly better in patients who harbor densely granulated somatotroph adenomas compared with those with sparsely granulated adenomas.[10] Sparsely granulated GH adenomas should be suspected in patients who present at an older age with a minimal elevation (1–5 ng/ml) of nonsuppressible GH levels. The main adverse events associated with the use of a somatostatin analog include transient abdominal cramps and malabsorptive diarrhea. There is an increased incidence of gall bladder sludge and stone formation, but these are not typically of clinical significance.[17] These long-acting somatostatin preparations are expensive[22] and require a meticulous reconstitution technique immediately before injection, compared with subcutaneous preparations. This renders a dedicated physician–nurse care-provider team essential for long-term care. It is anticipated that newer somatostatin receptor–selective analogs will prove to be even more effective[19] and easier to administer than currently available agents.

Impact of Therapy On Disease Outcomes. It is relatively recently that a consensus has started to emerge on the definition of a safe or acceptable degree of acromegaly control.[12] As such, the prospective examination of the impact of medical management on the rate of acromegaly-associated mortality has just started. Nevertheless, the results of retrospective studies support the role of adjunctive medical therapy in normalizing the level of IGF-I and mortality rates in patients with postoperative persistent disease.[20]

The impact of somatostatin analogs on acromegaly related comorbid complications has been best studied in impaired cardiovascular function. Glucose-suppressed GH levels lower than 1 ng/ml and age-normalized IGF-I levels are associated with a significant improvement in cardiac function.[3] In a multicenter prospective study, lantreotide therapy was associated with improvement in left ventricular hypertrophy and arrhythmias in patients with acromegaly.[15] In observational studies involving patients with persistently active disease, octreotide treatment was shown to reduce prostate size and volume[5] and to improve joint pain and active and passive articular mobility, while reducing joint thickness.[6] Similarly, several indices of the severity of sleep apnea improve favorably in response to long-term (>/= 6-month) octreotide-LAR treatment.[13] Glucose intolerance or diabetes can be favorably or more rarely, detrimentally influenced by somatostatin analogs,[14] emphasizing the need for longitudinal monitoring of glycemic control. Long-term somatostatin analog treatment has been associated with a significant reduction in insulin, triglyceride, and fibrinogen levels and improved intimal thickening in the carotid artery.[16] The impact of medical therapy on concrete cardiovascular end points, including myocardial ischemia or infarction, remains to be proven.

Somatostatin analogs alleviate many symptoms related to acromegaly including headaches, sweating, and arthralgias in nearly 75% of patients.[11] A reduction in the pituitary tumor size, however, is limited to a smaller subset of patients. The frequency and extent of tumor shrinkage appears to be greater (~70% and 30%, respectively) in patients who have not received previous therapy,[2] compared with those who have tumor remnants following pituitary surgery (~25% of patients).[11]

• Dopamine Agonists

Traditionally, nonselective dopamine agonists have been considered to be ineffective in adequately controlling acromegaly disease activity. In more recent studies, however, the authors have asserted that cabergoline, which has been shown to be a relatively more selective agonist of the dopamine D-2 receptor, may provide greater benefit than formerly used dopaminergic agents. In dose-adjusted studies, cabergoline was shown to suppress IGF-I below 300 ng/ml (the approximate normal value for a patient 30–40 years of age) in approximately 35% of patients depending on baseline IGF-I levels. As previously recognized, the concomitant excess of prolactin in patients with acromegaly is predictive of a better response to dopamine agonists, with an IGF-I level below 300 ng/ml attained in nearly 50% of such patients.[1,7] A significant degree of tumor shrinkage was demonstrated in a surprising 50% of patients. The addition of cabergoline to lanreotide in a subset of surgery- and octreotide-resistant cases results in significantly greater GH and IGF-I suppression than that attained using lanreotide alone.[16] Adverse effects include abdominal cramps and orthostatic hypotension. The results of these limited and uncontrolled studies indicate that the use of cabergoline for acromegaly may be worthy of consideration in the patient with treatment-resistant acromegaly. It should be considered as an adjunct in patients with persistently active disease, particularly when their disease is associated with a concomitant excess of prolactin.

• Growth Hormone Receptor Antagonists

The GH-receptor antagonists represent a relatively new class of therapy. The currently available agent was developed to compete with naturally occurring GH for binding with the GH receptor. Unlike native GH, however, this GH antagonist prevents the dimerization and signaling of the GH receptor, resulting in reduced production of IGF-I. Clinical trials have demonstrated that daily subcutaneous administration (10–20 mg) of pegvisomant results not only in reduction but in normalization of circulating IGF-I levels in nearly 80 to 90% of patients with acromegaly.[21] This agent, which recently was approved by the US Food and Drug Administration, appears to be well tolerated and does not produce any recognized significant adverse effects or tachyphylaxis after 1 year of continuous use.[21] The long-term safety and impact on pituitary tumor or tumor remnant growth is currently under investigation. At this time, pegvisomant should be considered for use in patients in whom surgery and medical therapy with somatostatin and/or dopamine agonists have proved ineffective or poorly tolerated (Fig. 1).

Figure 1. Treatment algorithm for acromegaly. The GH levels (given in ng/ml) represent postoperative values obtained after an oral glucose tolerance test or a random value obtained after 3 months of sandostatin–LAR treatment. Insulin-like growth factor–I levels should be standardized for age- and sex-specific differences. Cabergoline may be added to other pharmacological therapies at any stage if the levels of GH and IGF-I are not normalized. Short arrow pointing upward indicates elevated; GHa = growth hormone antagonist; Micro = microadenoma; N = normal; SSTA = somatostatin analog therapy; XRT = radiotherapy. (Click to enlarge figure)

• Selection of the Appropriate Agent

The influence of disease control on comorbid conditions has supported the use of medical therapy in patients who have undergone pituitary surgery and who continue to have elevated GH and IGF-I levels. In addition, medical therapy has been advocated for subsets of patients with acromegaly including those who refuse or cannot gain access to an experienced pituitary neurosurgeon, those who are poor candidates for surgery or anesthesia and those in whom no discrete pituitary lesion can be identified. For those with large invasive lesions that clearly cannot be completely resected, medical therapy should initially be advocated for at least 3 to 6 months. Depending on outcome, surgery may then be reconsidered (Fig. 1).

• Cost Considerations

Acromegaly is a disease that is accompanied by a significant economic burden. Longitudinal assessment of the economic costs relative to clinical and biochemical outcomes was examined over a 4-year period in 53 Canadian patients.[22] The mean annual cost per patient was CDN $8111 (95% confidence interval CDN $5848–$10,374). The GH-lowering medications constituted the highest component (nearly 38%) of the overall cost of disease management. It should be emphasized that, although surgical costs per patient were high (CDN $2800–$9200), the 4-year mean annual cost of surgery was approximately CDN $2400 less than the cost of medications. Furthermore, treatment of patients with macroadenomas cost considerably more (CDN $11,425) than that of patients with microadenomas (CDN $4442 annual cost). Although these are considerable costs, they are not significantly higher than those associated with other chronic diseases.[22]

• Conclusions

Acromegaly is often a chronic debilitating condition that, if left uncontrolled, is associated with increased rates of morbidity and mortality. The diagnosis is established by documenting autonomous GH hypersecretion and by imaging of the pituitary gland. Resection of the responsible pituitary adenoma has traditionally represented the cornerstone of disease management. This has recently been challenged, however, because a strict target of age-normalized IGF-I and a glucose-suppressed GH level lower than 1 ng/ml is difficult to achieve using surgery alone. Adjunctive therapy is frequently necessary because complete resection is not always achievable. This has prompted the view that primary medical therapy may be a suitable option to consider for some patients. Persistently active disease is documented to be associated with increased risks of morbidity and mortality. A suggested therapeutic algorithm is shown in Fig. 1. Somatostatin analogs are of particular benefit to those patients with persistently nonsuppressible levels of GH and/or elevated IGF-I levels after pituitary surgery or during the interim period following radiotherapy. They may also constitute primary therapy for those patients who decline surgery, are not likely to obtain a remission of their disease, or cannot tolerate surgery or radiation treatment. The use of GH antagonists alone or in combination with somatostatin analogs, although rational from the pharmacological point of view, remains to be proven.

---

References

1. Abs R, Verhelst J, Maiter D, et al: Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab 83:374–378, 1998

2. Bevan JS, Atkin SL, Atkinson AB, et al: Primary medical therapy for acromegaly: an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-I, and tumor size. J Clin Endocrinol Metab 87:4554–4563, 2002

3. Clayton RN: Cardiovascular function in acromegaly. Endocr Rev 24:272–277, 2003

4. Colao A, Marzullo P, Lombardi G, et al: Effect of a six-month treatment with lanreotide on cardiovascular risk factors and arterial intima-media thickness in patients with acromegaly. J Clin Endocrinol 146:303–309, 2002

5. Colao A, Marzullo P, Spiezia S, et al: Effect of two years of growth hormone and insulin-like growth factor-I suppression on prostate disease in acromegalic patients. J Clin Endocrinol Metab 85:3754–3761, 2000

6. Colao A, Marzullo P, Vallone G, et al: Ultrasonographic evidence of joint thickening reversibility in acromegalic patients treated with lanreotide for 12 months. Clin Endocrinol 51: 611–618, 1999

7. Cozzi R, Attanasio R, Barausse M, et al: Cabergoline in acromegaly: a renewed role for dopamine agonist treatment? Eur J Endocrinol 139:516–521, 1998

8. Danila DC, Haidar JN, Zhang X, et al: Somatostatin receptorspecific analogs: effects on cell proliferation and growth hormone secretion in human somatotroph tumors. J Clin Endocrinol Metab 86:2976–2981, 2001

9. Ezzat S, Forster MJ, Berchtold P, et al: Acromegaly. Clinical and biochemical features in 500 patients. Medicine 73: 233–240, 1994

10. Ezzat S, Kontogeorgos G, Redelmeier DA, et al: In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide. Eur J Endocrinol 133: 686–690, 1995

11. Ezzat S, Snyder PJ, Young WF, et al: Octreotide treatment of acromegaly. A randomized, multicenter study. Ann Intern Med 117:711–718, 1992

12. Giustina A, Barkan A, Casanueva FF, et al: Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 85:526–529, 2000

13. Ip MS, Tan KC, Peh WC, et al: Effect of Sandostatin LAR on sleep apnoea in acromegaly: correlation with computerized tomographic cephalometry and hormonal activity. Clin Endocrinol 55:477–483, 2001

14. Koop BL, Harris AG, Ezzat S: Effect of octreotide on glucose tolerance in acromegaly. Eur J Endocrinol 130:581–586, 1994

15. Lombardi G, Colao A, Marzullo P, et al: Improvement of left ventricular hypertrophy and arrhythmias after lanreotide-induced GH and IGF-I decrease in acromegaly. A prospective multi-center study. J Endocrinol Invest 25:971–976, 2002

16. Marzullo P, Ferone D, Di Somma C, et al: Efficacy of combined treatment with lanreotide and cabergoline in selected therapyresistant acromegalic patients. Pituitary 1:115–120, 1999

17. Newman CB, Melmed S, Snyder PJ, et al: Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients—a clinical research center study. J Clin Endocrinol Metab 80:2768–2775, 1995

18. Reubi JC, Landolt AM: The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status. J Clin Endocrinol Metab 68:844–850, 1989

19. Saveanu A, Gunz G, Dufour H, et al: Bim-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotideresistant human GH-secreting adenomas. J Clin Endocrinol Metab 86:140–145, 2001

20. Swearingen B, Barker FG II, Katznelson L, et al: Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 83:3419–3426, 1998

21. van der Lely AJ, Hutson RK, Trainer PJ, et al: Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 358:1754–1759, 2001

22. Wilson LS, Shin JL, Ezzat S: Longitudinal assessment of economic burden and clinical outcomes in acromegaly. Endocr Pract 7:170–180, 2001

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

January 22, 2009 — Nonepileptic paroxysmal events are behavioral, motor, or sensory episodes that do not result from abnormal cortical electrical activity. They can mimic any type of epileptic seizures including simple partial, complex partial, and generalized tonic-clonic seizures. Nonepileptic paroxysmal events may be physiological or psychogenic in nature. In clinical practice, the most common imitators of epileptic seizures are syncope and psychogenic seizures, but transient ischemic attacks, migraine, movement disorders, and metabolic disturbances must be considered at times in the differential diagnosis. In most cases, the clinical history is enough to make a correct diagnosis. The clinical features suggestive of various types of nonepileptic paroxysmal events, together with useful diagnostic tests, will be reviewed.

The differential diagnosis of epileptic seizures is very broad, partly because the symptomatology of epileptic seizures is varied, depending on the eloquent cortical areas activated by the epileptic activity (symptomatogenic zone). There is a great amount of diseases which can produce focal neurological symptoms and signs, occurring repeatedly in a paroxysmal way, not unlike epileptic seizures, and which can be mistaken for epilepsy. Yet, to make a definite diagnosis of epilepsy, it is necessary to demonstrate the epileptiform activity associated with the recurrent attacks. Nonepileptic seizures are behavioral, sensory, and motor events that are not associated with epileptiform activity. However, in the case of some physiologic nonepileptic seizures, like syncope, abnormal electrical activity may be identified at the time of the event. Nonepileptic seizures can mimic any type of epileptic seizures.

The limited duration, the presence of an aura, the postictal confusion, and the stereotyped nature of symptoms are some of the clinical features of epileptic seizures that help to make a correct diagnosis. In the majority of cases, a diagnosis can be made from a properly taken clinical history. A detailed description of the symptoms and signs exhibited during the paroxysmal episode is essential to reach a correct diagnosis and classify the epileptic seizures. Accordingly, it is necessary to obtain information from the patient and witnesses, including:

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

January 21, 2009 — Syringomyelia poses special challenges for the clinician because of its complex symptomatology, uncertain pathogenesis, and multiple options of treatment. The purpose of this study was to classify intramedullary cavities according to their most salient pathological and clinical features.

The use of a disease-based classification of syringomyelia facilitates diagnosis and the interpretation of MR imaging findings and provides a guide to treatment.

Previous attempts to classify syringomyelia have been based on presumed mechanisms of pathogenesis.[1-3,5,6,20] These classifications have been useful and have helped to shape surgical treatment. However, with the advent of MR imaging it has become evident that some concepts of pathogenesis are no longer tenable. Chief among these is the hypothesis that syrinx formation depends on the forceful diversion of CSF from the fourth ventricle into the central canal of the spinal cord.[7,19,20]

Contributing to the difficulty of defining mechanisms of syrinx formation has been the general lack of information on pathological features. Although Netsky[15] has reported on eight autopsy cases, with few exceptions most studies prior to 1990 were case reports. In recent years, reports have appeared that help to clarify the pathological features of spinal cord cavitation.[8,10] These data, taken together with MR imaging correlates, permit a reclassification of syringomyelia based on morbid anatomy.

Tubular enlargements of the spinal cord that are not due to intramedullary tumors have been classified as follows on the basis of pathological findings:[10]

1. Dilations of the central canal that are anatomically continuous with the fourth ventricle (communicating syringomyelia);

2. Dilations of the central canal that do not communicate with the fourth ventricle (noncommunicating syringomyelia)

3. Extracanalicular syringes that originate in the spinal cord parenchyma and do not communciate with the central canal or fourth ventricle (primary parenchymal cavitations).

These lesions are distinguished from two other types of cavitation:

1. Atrophic syringes occurring with myelomalacia (syringomyelia ex vacuo)

2. Neoplastic cysts.[12]

• Communicating Central Canal Dilations

Communicating syringes are caused by obstructions of the CSF pathways distal to the outlets of the fourth ventricle (Fig. 1). In typical cases, there is generalized enlargement of all four cerebral ventricles, and the central canal participates in the hydrocephalic process like a “fifth ventricle.” Causative factors include postmeningitic and posthemorrhagic hydrocephalus, complex hindbrain malformations, such as Chiari II malformation and encephalocele, and Dandy-Walker cysts. An experimental model of communicating syringomyelia can be produced by injecting kaolin into the cisterna magna.[4,21]

On histological examination, communicating syringes appear as simple dilations of the central canal, lined wholly or partially by ependyma (Fig. 1A). In acquired examples, the length of the cavity is defined caudally by central canal stenosis (Fig. 1B), which is an age-related phenomenon affecting the majority of normal individuals by the early years of adult life.[13] Holocord enlargements are most often of congenital origin and may be anatomically continuous with caudal lesions such as myelomeningocele. With distension of the central canal, the ependymal epithelium becomes stretched and denuded. Nevertheless, despite the large size of some communicating syringes, these lesions are much less prone than noncommunicating syringes to rupture paracentrally, and this may explain why a significant number of communicating syringes remain asymptomatic throughout life or are associated with only minor neurological findings.[10,12] Figure 2 illustrates the MR imaging correlates of communicating syringomyelia.

Figure 1. Diagrammatic and photomicrographic depictions of communicating syringomyelia. Left: Diagram illustrating the pathological findings obtained in a 49-year-old male with post-meningitic hydrocephalus, basilar arachnoiditis, and syringomyelia. The syrinx is anatomically continuous with the enlarged fourth ventricle (4th) and its length has been determined by CCS. Right: Photomicrographs of specimens obtained in the same patient. H & E. A: Axial section obtained through the syrinx at T-1, showing a central cavity lined by ependyma. Original magnification x 10. B: Axial section obtained immediately below the syrinx at T-10, demonstrating occlusion of the central canal (arrow). Original magnification x 40. (Click to enlarge figure)

Figure 2. Magnetic resonance imaging studies demonstrating communicating syringomyelia of the cervical spine in a 58-year-old male with posthemorrhagic hydrocephalus and syringomyelia. Left: Sagittal image demonstrating that the syrinx is continuous with the fourth ventricle. Right: Axial image revealing a symmetrically enlarged central cavity. (Click to enlarge figure)

• Noncommunicating Central Canal Dilations

Dilations of the central canal that do not communciate with the fourth ventricle are associated with obstructions of the CSF pathways at or below the foramen magnum. Causative factors include the Chiari I malformation, basilar invagination, spinal arachnoiditis, extramedullary compressions, tethered cord, and acquired tonsillar herniation. There is accumulating evidence that the formation of noncommuniating syringes depends on an increase of the arterial pulse wave in the spinal subarachnoid space that is sufficient to force CSF through anatomically continuous perivascular and interstitial spaces into the central canal of the spinal cord.[14,16-18] An experimental model of noncommunicating syringomyelia can be produced by injecting kaolin into the central canal and regional meninges.[14,18]

On histological examination, noncommunicating syringes appear as isolated cavities that are defined rostrally and caudally by central spinal canal stenosis (Fig. 3). These cavities tend to be complex lesions and are characterized histologically by extensive areas of ependymal denuding, paracentral dissection, and the formation of intracanalicular septae.[10] In contrast to communicating syringes, which rarely rupture paracentrally, noncommunicating syringes exhibit a propensity for dissecting into the spinal cord parenchyma (Fig. 4). Parenchymal dissections occur preferentially into the dorsolateral quadrant of the spinal cord and may extend through the pial surface to communicate with the subarachnoid space. Neurological findings can often be correlated with the anatomy of cavitation demonstrated on MR imaging (Figs. 5 and 6).

Figure 3. Diagrammatic and photomicrographic representations of noncommunicating central canal dilation. Left: Diagram illustrating the pathological findings obtained in a 66-year-old male with syringomyelia occurring in association with basilar invagination and a Klippel-Feil anomaly. The syrinx is defined rostrally and caudally by CCS and was asymptomatic during life. Right: Photomicrographs of specimens obtained in the same patient. H & E, original magnification x40. A: Axial section immediately rostral to the syrinx showing occlusion of the central canal (arrow). B: Axial section obtained through the syrinx at T-3, demonstrating dilation of the central canal with some denuding of the ependyma. (Click to enlarge figure)

Figure 4. Diagrammatic and photomicrographic depictions of noncommunicating central canal dilation. Left: Diagram illustrating the pathological findings obtained in a 62-year-old female with a Chiari I malformation and syringomyelia. The syrinx is defined rostrally and caudally by CCS. At C-7, the syrinx has ruptured into the dorsal white matter columns and dissected rostrally above the original cavitation. Clinical findings while the patient was alive included numbness and clawing of the left hand, impaired position sense, and spastic weakness of the legs. Right: Photomicrographs of specimens obtained in the same patient. H &E, original magnification x40. A: Axial sections of the spinal cord obtained at C-4, showing an extracanalicular cavitation of the dorsal white matter columns. The central canal is stenotic (arrow). B: Axial section through the syrinx obtained at C-7, demonstrating an ependymal-lined cavity that has ruptured through the dorsal root entry zone on the left to communicate with the subarachnoid space. (Click to enlarge figure)

Figure 5. Magnetic resonance images demonstrating noncommunicating central canal dilation of the cervical spine in a 42-year-old female with a Chiari I malformation and syringomyelia. Clinical findings were limited to fatigue and weakness of the extremities and hyperreflexia. Left: Sagittal image revealing that the syrinx is separated from the fourth ventricle by a long, syrinx-free segment of spinal cord. Right: Axial image obtained through syrinx at T-1, demonstrating a symmetrically enlarged central cavity. (Click to enlarge figure)

Figure 6. Magnetic resonance images demonstrating noncommunicating central canal dilation of the cervical spine in a 24-year-old female with a Chiari I malformation and syringomyelia. Neurological findings included a decreased left-sided corneal reflex, impaired pain and temperature sensation involving all three divisions of the left trigeminal nerve, weakness of the left arm and leg, patchy analgesia of the left arm, and impaired pain and temperature sensation below T-2 on the right. Upper Left: Sagittal image revealing a noncommuniating syrinx (C-1 to T-2) and a Chiari I malformation. Upper Right: Axial image obtained through syrinx at C-5, demonstrating a symmetrically enlarged central cavity. Lower Left and Right: Axial images obtained above C-4 demonstrating that the syrinx has expanded into the left dorsolateral quadrant of the spinal cord (lower left) and dissected rostrally to enter the medulla on the left side (lower right). (Click to enlarge figure)

• Primary Parenchymal Cavitations

These lesions consist of tubular cavitations of the spinal cord that originate in the parenchyma and do not communicate with the central spinal canal or fourth ventricle (Fig. 7). A distinguishing feature of this type of syringomyelia is its association with conditions that injure the spinal cord tissue. Common causative factors include trauma, ischemia/infarction, and spontaneous intramedullary hemorrhage. Although the mechanism by which parenchymal cavities fill and distend is incompletely understood, current evidence suggests that arachnoiditis occurring at the time of injury produces a regional CSF block that forces fluid from the subarachnoid space into the interstitial spaces of the spinal cord.[4,10]

Figure 7. Diagrammatic and photomicrographic representations of primary parenchymal cavitation. Left: Diagram of pathological findings obtained in a 62-year-old female with posttraumatic syringomyelia who had been paraplegic for 23 years following a motor vehicle accident. The syrinx occupies three quadrants of the spinal cord and does not communicate with the central canal. Right: Photomicrographs of sections obtained in the same patient. H & E. A: Axial sections obtained through the syrinx at T-2, showing a large, irregular parenchymal cavity. The central canal is occluded (arrow). Original magnification x10. B: Axial section obtained through the injury site at T-8, demonstrating a glial scar with hemosiderin-laden macrophages (larger arrow) and a stenotic central canal (smaller arrow). Original magnification x 40. (Click to enlarge figure)

Primary parenchymal cavitations typically arise in the watershed area of the spinal cord, dorsal and lateral to the central canal. Like the paracentral dissections of central canal syringes, these lesions are lined by glia or fibroglial tissue, and they are characterized histologically by varying degrees of necrosis, neuronophagia, and wallerian degeneration.[10] A particularly common histological finding is the presence of hemosiderin-laden macrophages in the walls of cavities caused by trauma or hemorrhage. Figure 8 illustrates the MR imaging correlates of this type of syringomyelia.

Figure 8. Magnetic resonance images demonstrating primary parenchymal cavitation of the cervical spine in a 43-year-old female with posttraumatic syringomyelia and burning dysesthesias of the left arm and upper chest. Neurological findings included weakness of the left arm and leg, areflexia of the left arm, and impaired sensation with trophic changes from C-5 to T-4 on the left side. Upper Left: Sagittal image revealing congenital stenosis of the cervical spine and noncommunicating syringomyelia (C-4 to C-7). Upper Right: Horizontal image demonstrating lateralization of the syrinx to the left hemicord. Lower Left: Axial image obtained at C-5 demonstrating that the syrinx occupies the left dorsolateral quadrant of the spinal cord. (Click to enlarge figure)

• Atrophic Cavitations (Syringomyelia Ex Vacuo)

Degenerative changes occurring in conjunction with spinal cord atrophy can lead to the formation of microcysts, intramedullary clefts, and localized dilations of the central spinal canal. Atrophic cavitations do not propagate, presumably because of the absence of a filling mechanism, and are caused by the loss of parenchymal tissue (syringomyelia ex vacuo). On MR imaging, these lesions appear as nondistended cavities confined to the area of myelomalacia (Fig. 9).

Figure 9. Magnetic resonance images demonstrating syringomyelia ex vacuo of the cervical spine in a 76-year-old male with progressive myelopathy. Left: Sagittal image revealing cervical spondylosis and a small intramedullary cleft within an area of myelomalacia (arrow). Right: Axial image revealing a transversely collapsed cavity (arrow) that extends into the dorsal columns of the spinal cord. (Click to enlarge figure)

• Neoplastic Cavitations

Syrinx-like cavities can be formed by the cystic degeneration of intramedullary tumors such as astrocytomas, ependymomas, and other less common neoplasms. The necrotic process begins centrally and tends to extend rostrally or caudally from the poles of the tumor. Neoplastic cysts contain proteinaceous fluid that is quite different from CSF, and the walls of the cyst are lined by tumor or tightly packed glial tissue around a mural nodule. The diagnosis is established by performing contrast-enhanced MR imaging (Fig. 10).

Figure 10. Magnetic resonance images demonstrating a neoplastic cyst of the cervical spine in a 21-year-old female with a cystic intramedullary ependymoma. The tumor is difficult to see on a noncontrast-enhanced image (left) but enhances brilliantly after the adminsitration of gadolineum (right). (Click to enlarge figure)

Table 1 provides a classification of syringomyelia based on pathological findings and MR imaging correlates. The separation of syringes into communicating, noncommunicating, and atrophic types implies mechanisms of pathogenesis. Causative factors have been summarized according to standard nomenclature. The inclusion of neoplastic cavitations in this classification system is meant to emphasize their importance in the differential diagnosis of syringomyelia rather than to suggest any pathological similarities.

Table I. Classification of syringomyelia

Type	Comment
Communicating syringomyelia	Central canal dilations Communicating hydrocephalus (posthemorrhagic, postmeningitic) Complex hindbrain malformations (Chiari II, encephalocele) Dandy-Walker cyst
Noncommunicating syringomyelia	Central canal/paracentral syringes Chiari malformations Basilar invagination Spinal arachnoiditis (posttraumatic, postmeningitic) Extramedullary compressions (spondylosis, tumors, cysts) Tethered cord Acquired tonsillar herniation (hydrocephalus, intracranial mass lesions,craniosynostosis)
Primary parenchymal cavitations	Spinal cord trauma Ischemia/infarction Intramedullary hemorrhage
Atrophic cavitations (syringomyelia ex vacuo)	Degenerative changes occurring in conjunction with spinal cord atrophy can lead to the formation of microcysts, intramedullary clefts, and localized dilations of the central spinal canal. Atrophic cavitations do not propagate, presumably because of the absence of a filling mechanism, and are caused by the loss of parenchymal tissue (syringomyelia ex vacuo). On MR imaging, these lesions appear as nondistended cavities confined to the area of myelomalacia (Fig. 9).
Neoplastic cavitations	Syrinx-like cavities can be formed by the cystic degeneration of intramedullary tumors such as astrocytomas, ependymomas, and other less common neoplasms. The necrotic process begins centrally and tends to extend rostrally or caudally from the poles of the tumor. Neoplastic cysts contain proteinaceous fluid that is quite different from CSF, and the walls of the cyst are lined by tumor or tightly packed glial tissue around a mural nodule. The diagnosis is established by performing contrast-enhanced MR imaging (Fig. 10).

The use of a disease-based classification of syringomyelia facilitates diagnosis and the interpretation of MR imaging findings. With this system, it is possible in most cases to establish clinicopathological correlations (see Figs. 3-8). The ability of MR imaging to distinguish between communicating, noncommunicating, and atrophic syringes has treatment implications. For example, communicating syringes are generally treated by placing ventricular shunts. In the case of noncommunicating syringes, the goal of surgery is to relieve the CSF obstruction, and shunt placement is reserved as a secondary procedure.[9,11] Atrophic syringes are obviously not treated surgically. Overall, although no classification is truly ideal, the use of a disease-based system provides a solid foundation for diagnosis and treatment.

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