and cantrell divided the process into two steps. in the first step, changes in the circumference of the cranium are calculated from the phase difference between a sinusoidal excitatory signal, delivered with a piezo-transducer, and the response that is received at a distance with another piezotransducer. in the second step, changes in icp are calculated as a product of the changes in the cranium circumference and the elasticity constant of the skull that has been determined earlier by causing known changes in icp while measuring the cranium circumference. none of the aforementioned methods has been properly validated in relevant clinical populations, and their accuracy is unknown. one may assume however that it would be comparable to the ultrasound time-of-the-flight methods, and thus insufficient for a routine clinical use. luna innovations incorporated (nasdaq: luna) developed en-tact system, an ultrasound device for monitoring compartment syndrome. the technology was claimed to have applications for raised intracranial pressure. based on research from the nasa ames research center, the company used ultrasound to measure skull diameter changes caused by icp changes. however, skull changes are tiny and only indirectly related to icp, raising questions about the accuracy and calibration. tympanic membrane displacement tympanic membrane displacement (tmd) technique, proposed nearly twenty years ago by marchbanks exploits the effect of intracranial pressure on the acoustic reflex, i.e. a reflex contraction of the stapedius and tensor tympani muscles in response to a sound. normally, vibrations of the tympanic membrane (eardrum) elicited by acoustic stimuli are transmitted through the chain of ossicles (malleus, incus, and stapes) in the middle ear to the oval window of the cochlea. vibrations of the footplate of stapes transmit through the oval window to the perilymph, which in turn causes the endolymph, the basilar membrane, and the organ of corti to vibrate, activating ultimately the acoustic sensor cells, the inner hair cells of the organ of corti. the transfer function of this complex mechanical system under physiological conditions is modulated by the action of two small muscles of the middle ear, the tensor tympani, and stapedius. the tensor tympani arises from the cartilaginous portion of the auditory tube and the osseous canal of the sphenoid and, having sharply bent over the extremity of the septum, attaches to the manubrium of the malleus (hammer); its contraction pulls the malleus medially, away from the tympanic membrane, which tenses the membrane. the stapedius, which emerges from the posterior wall of the tympanic cavity of the middle ear and inserts into the neck of the stapes (stirrup), prevents excess movements of the stapes by pulling it away from the oval window. the action of either muscle, therefore, dampens vibrations of the ossicles and reduces the amplitude of transmitted sounds for up to 20 db. the muscles normally contract in response to vocalization, jawing and loud external sounds, which is accompanied by a small but measurable displacement of the eardrum from its initial position. because cerebrospinal fluid and perilymph communicate through the cochlear aqueduct, an increase in intracranial pressure is directly transmitted to the footplate of the stapes, changing its initial position and affecting thereby the direction and magnitude of the displacement of the eardrum in response to a sound. the displacement can be measured with common tympanometers used for impedance audiometry that are portable and relatively inexpensive and easy to use (particularly the modern, computerized tympanometers with fully automated measurement procedure). inward displacement (negative peak pressure on an audiogram) is suggestive of high, and outward of normal or low icp. the direction and magnitude of tmd, however, depend not only on the initial position of stapes but also on numerous other factors that affect the acoustic impedance (integrity of the eardrum, condition of the ossicles, patency of the eustachian tube, pressure and eventual presence of fluid or other masses in the middle ear) or the strength of the acoustic reflex (physiological variability of the reflex threshold, functional integrity of the cochlear and facial nerves, degree of eventual sensory hearing loss). in addition, the assumption that the pressure of perilymph is equal to icp does not hold if the patency of the cochlear aqueduct is compromised, which is often the case in elderly subjects. accuracy of tmd estimates of icp was found to be at the order of ±15mmhg, which is not sufficient for a reliable quantitative assessment of icp in clinical practice. an interesting method that involves direct manipulations on the tympanic membrane rather than relying on the acoustic reflex was proposed as one of the embodiments of a us patent by ragauskas. first, a measurement of the position of the tympanic membrane needs to be obtained while icp is zero (denoted as the baseline position). equalization of icp to the atmospheric pressure according to the inventor can be achieved non-invasively by tilting the head up, or the measurement can be taken during a neurosurgical operation. later on, icp can be measured by exerting an external pressure to the tympanic membrane and applying simultaneously the same pressure onto the oval window and inner ear (e.g. through the eustachian tube) until the eardrum is moved back to the baseline position, which will happen when the exerted external pressure equals icp. no data is provided in the patent nor is available from other sources that could support the utility of the concept in clinical practice. otoacoustic emission tmd fails to provide accurate estimates of icp mostly because the acoustic impedance and its changes due to the acoustic reflex are dominantly determined by the structures and functional properties of the middle ear, and only marginally influenced by changes in icp. a measurable acoustic phenomenon that originates in the inner ear would, at least in theory, allow for more precise assessment of the pressure of the peri- and endo-lymph, and consequently, of icp. otoacoustic emission (oae), which is a sound generated by subtle oscillations of the endo- and perilymph caused by contractions of the outer hair cells of the inner ear in response to a loud sound, seems to offer such a possibility. the sound is transmitted to the stapes, and further through the ossicles, to the tympanic membrane from which it can be detected with a sensitive microphone inserted into the ear canal. oae is used in clinical practice to test for hearing deficits in babies and children who are too young to cooperate. the equipment can be made portable and is relatively easy to use. two approaches have commonly utilized that increase the unfavorable signal-to-noise ratio and facilitate extraction of the oae waveform: transient evoked otoacoustic emission (teoae) and distortion product otoacoustic emission (dpoae). in a recent us patent issued to meyerson and colleagues proposed the use of both the teoae and dpoae for measurement of icp. teoae is used first to determine the optimum oae response frequency, after which the pair of pure tones is deployed in a dpoae paradigm such that the cubic distortion product frequency equals the optimum response frequency while the ratio of frequencies f2/f1 is set to 5:4, and of intensities i2/i1 to 6:5. the inventors also proposed formulae that relate icp to the intensity or phase of the measured oae signal, and described how the other physiological signals or behaviors that are known to affect icp such as small oscillations of icp with each heartbeat, respiration, or posture changes, can be used to confirm the validity of the obtained measurements (e.g. the absence of modulation of the measured oae phase with respiration may indicate occlusion of the cochlear aqueduct, in which case oae cannot provide any information about icp). there is little data up to date about the clinical utility or accuracy of otoacoustic emission as a measure of icp. a pilot study of frank and colleagues that evaluated different modalities of oae in 12 healthy volunteers and 5 patients with implanted ventricular catheters for direct icp monitoring revealed that increased icp or conditions known to increase icp (e.g. posture changes, abdomen compression, coughing) were associated with notable decreases (between -2.1 and -7.9spl) in intensity of the evoked oae. all results were however reported only as group averages, and no attempt was made to derive a quantitative one-to-one relation between the oae intensity and icp. this method as all other correlation-based approaches cannot be used for absolute icp value measurement because of the impossibility of individual calibration. ocular measurements eye provides another possible window into the pressure changes in the intracranial compartment thanks to the fact that the space between the optic nerve and its sheath is a continuation of the subarachnoid space, and is consequently filled with cerebrospinal fluid whose pressure is equal to intracranial pressure. intracranial hypertension will thus manifest in an increased diameter of the optic nerve sheath and will impede the blood flow through the central retinal vein that courses within the sheath, along and in part inside of the optical nerve. the impediment of venous return causes visible changes in the eye fundus (venous engorgement, and papilledema, i.e. swelling and elevation of the optic nerve disc) that can be observed with an ophthalmoscope and have therefore been used by clinicians for more than a century as signs of increased icp. quantitative assessment of icp can be made noninvasively in two different ways: by measuring changes in diameter of the optic nerve sheath with an appropriate technique (ultrasound or mri), or by using ophthalmodynamometry to determine the pressure in the central retinal vein, which is normally slightly higher (1- 2mmhg) than icp. intracranial hypertension also induces changes at the cellular or axonal level such as the swelling of the fibers of the optic nerve that form the innermost layer of the retina (so-called nerve fiber layer – nfl). the information provided by the classic ophthalmoscopy is however only qualitative and may be inconclusive during early phases of intracranial hypertension since it usually takes between two and four hours from the onset of icp elevation for a papilledema to develop. a patented method that utilizes optical coherence tomography to measure the thickness of the nerve fiber layer and infers icp from it laid claims of being able to detect the ih-induced thickening of the retina shortly after the onset of ih, but there has been no data that would support the claims or clarify the relationship between the nfl thickness and levels of icp. optic nerve sheath diameter the use of optic nerve sheath diameter (onsd) for the assessment of icp dates back to 1987 when cennamo and colleagues demonstrated a linear relationship between icp and the sheath diameter measured with a trans-orbital ultrasound probe in an a-scan mode (principally equivalent to the time-of-the-flight measurements of the cranium diameter). the original measurement method was technically difficult and unreliable because of the nearly coaxial alignment of the optic nerve and propagation axis of the ultrasound wave, but the precision was significantly improved with the use of b-scan (or planar) ultrasound which provided longitudinal cross-section images of the optic nerve and its sheath. since then, the method has been successfully validated in several relatively large studies that included patients with severe head trauma, hydrocephalus, intracranial hemorrhage or stroke, liver failure, and climbers with acute mountain sickness. while the onsd can at any given point along the optic nerve be measured with a precision of <1mm, the reliability of derived icp levels is plagued by inter-individual variability and the dependence of onsd magnitude on the point along the nerve at which the measurement was taken. almost all validation studies so far have recommended that onsd to be used for identification of patients with intracranial hypertension that requires treatment (icp>20mmhg, i.e. onsd>5mmhg) rather than for a measurement of icp. onsd measurement by ultrasound is not as precise as invasive icp measurement but may be useful if invasive measurement is not available. ophthalmodynamometry or the measurement of the retinal venous outflow pressure (vop) performed by applying external pressure on the sclera, for example with a spring plunger, while observing the retinal vessels through an ophthalmoscope. the pressure is gradually increased until the central retinal vein begins to pulsate, which happens at the point when the applied external pressure nears the vop and is approximately equal to icp. the original method was described in 1925 by baurmann and belongs to the public domain, but several modifications have been recently patented that combine the classic ophthalmodynamometry