non-invasive measurement of intracranial pressure non-invasive measurement of intracranial pressure increased intracranial pressure (icp) is one of the major causes of secondary brain ischemia that accompanies a variety of pathological conditions, most notably traumatic brain injury (tbi), strokes, and intracranial hemorrhages. it can cause complications such as vision impairment due to intracranial pressure (viip), permanent neurological problems, reversible neurological problems, seizures, stroke, and death. however, aside from a few level i trauma centers, icp monitoring is rarely a part of the clinical management of patients with these conditions. the infrequency of icp can be attributed to the invasive nature of the standard monitoring methods (which require insertion of an icp sensor into the brain ventricle or parenchymal tissue). additional risks presented to patients can include high costs associated with an icp sensor's implantation procedure, and the limited access to trained personnel, e.g. a neurosurgeon. alternative, non-invasive measurement of intracranial pressure, non-invasive methods for estimating icp have, as a result, been sought. non-invasive intracranial pressure measurement methodspurposemeasure icp correlation-based approaches many approaches to non-invasive icp estimation are based on the idea that something in the human head's anatomical structure or in the intracranial and extracranial physiology correlates with icp. "correlation-based" approaches can reflect factors associated with icp only with limited accuracy (expressed by systematic error) and precision (expressed by the standard deviation of random error). measuring absolute icp value is limited by the need for individual patient-specific calibration. absolute icp values in mmhg or other units are needed to determine the correct patient treatment. the only accurate, precise, and patient-specific, calibration-free, non-invasive, absolute icp value measurement method relies not on the correlation, but on direct icp and extracranial pressure comparison principle. two depth transorbital doppler (tdtd) an innovative method using a two-depth transorbital doppler (tdtd) of intracranial pressure quantitative absolute (icp) value measurement relies on the same fundamental principle that is used to measure blood pressure with a sphygmomanometer. a sphygmomanometer works using a pressure balance principle - an air-filled pressure cuff wrapped around the arm compresses the brachial artery to a point where blood can no longer flow. externally applied pressure is equal to systolic blood pressure in this case. the examiner slowly releases the air from the cuff and uses a stethoscope to listen for the return of blood flow. at the pressure balance point, where the pressure in the cuff equals systolic artery pressure, a ‘whooshing’ noise can be heard as blood flows through the artery again. pressure balance based a non-invasive blood pressure meter does not need a patient-specific calibration. the tdtd method uses doppler ultrasound to translate the pressure balance principle of blood pressure measurement with a sphygmomanometer to the measurement of icp. the ophthalmic artery (oa), a unique vessel with intracranial and extracranial segments, is used as a pressure sensor and as a natural pair of scales for absolute icp value in mmhg or mmh2o measurement. blood flow in the intracranial oa segment is affected by intracranial pressure, while flow in the extracranial (intraorbital) oa segment is influenced by the externally applied pressure (pe) to the eyeball and orbital tissues. as with a sphygmomanometer, a special pressure cuff is used - in this case, to compress the tissues surrounding the eyeball and also intraorbital tissues surrounding the extracranial segment of oa. external pressure changes the characteristics of blood flowing from inside the skull cavity into the eye socket. in place of the stethoscope, a doppler ultrasound beam measures the blood flow pulsations in intracranial and extracranial segments of the ophthalmic artery. the non-invasive icp meter based on this method gradually increases the pressure over the eyeball and intraorbital tissues so that the blood flow pulsation parameters in two sections of the oa are equal. at this pressure balance point, the applied external pressure (pe) equals the intracranial pressure (icp). this measurement method eliminates the main limiting problem of all other non-successful approaches to non-invasive icp measurement, primarily the individual patient calibration problem. direct comparison of arterial blood pressure (abp) and externally applied pressure is the basic arterial blood pressure measurement principle, which eliminates the need for individual calibration. the same calibration-free fundamental principle is used in the tdtd non-invasive icp absolute value measurement method. the mean value of oa blood flow, its systolic and diastolic values, pulsatility and other indexes are almost the same in both oa segments in the point of balance when icp equals pe. as a result of that, all individual influential factors (abp, cerebrovascular auto-regulation impairment, individual pathophysiological state of patience, individual diameter, and anatomy of oa, hydrodynamic resistance of eyeball vessels, etc.) do not influence the balance of icp equaling pe and, as a consequence, such natural “scales” do not need calibration. ragauskas a. et al. have already published the statistically significant results of a prospective clinical study on assessment of the accuracy and precision of proposed non-invasive absolute icp value measurement method. the study shows that proposed method is the only quantitative noninvasive icp absolute value (mmhg) measurement method which does not need an individual patient-specific calibration. high accuracy, precision, sensitivity and specificity of the proposed method are fully acceptable for clinical practice and for very wide applications in neurology, transplantology, intensive care, sports medicine, aerospace medicine, and combat casualty care. this method was further developed by the company vittamed ltd along with consortium partners in eu fp7 projects brainsafe brainsafe, brainsafe ii, and tbicare. ultrasound time of the flight techniques the majority of patented methods for noninvasive monitoring of icp are based on an assumption that changes in icp affect the physical dimensions and/or acoustic properties of the cranial vault or intracranial structures (dura, brain tissue, brain ventricles, and/or intracranial vessels). the common drawback of all these methods is that they measure only relative changes of icp as referenced to a baseline measurement during which absolute icp is known, i.e. the ultrasound readouts need to be calibrated on each subject against an invasive measurement. ultrasound ‘time of the flight’ methods for non-invasive icp monitoring have not been extensively validated and currently, the majority of them do not seem to be accurate enough for a routine clinical use. their original formulations usually do not specify locations for the transducer's placement and do not address how the intentional or accidental use of different locations and/or angles of the transducers will affect the reliability of icp estimates. it has also remained unexplored how the measurements are affected by the presence of intracranial pathological masses on the path of the ultrasound wave, or by brain masses shifts. cranium diameter dimensions of the cranium or its structures are determined with the ultrasound “time-of-the-flight” technique that measures the transit time of an ultrasound wave and its (potentially multiple) echoes on their path through the cranium and calculates the corresponding distance(s) using known ultrasound propagation velocities in different tissues (e.g. bone, brain, or fluid). unfortunately, a reproducible quantitative relationship between the diameter of the cranium and icp could not be established because icp-induced changes in the cranium diameter are very small compared to the inter-individual variability of skull sizes, shapes and thicknesses. thickness of the dura the method claims that icp can be inferred from the thickness of the dura mater that is estimated from interference echoes of an ultrasonic wave. the utility of the method was successfully confirmed on four healthy subjects and four patients with intracranial hypertension, but larger validation studies have never been conducted as the method failed to attract enough interest among clinicians. this method also needs a calibration to the individual patients. cerebral ventricle michaeli proposed that icp should be inferred from the magnitude and shape of pulsations of the third ventricle synchronous with the cardiac cycle or respiration, where the pulsations are measured along the propagation axis of an ultrasound wave. the method so far has not been independently validated, and the author provides no exact data from which one could estimate the accuracy of the method. however, the discussion in the body of the patent document suggests that the method is able to distinguish among three ranges of icp (<20, 20–40 and >40mmhg) but cannot provide an exact value of icp within the range because of the impossibility of the calibration to the individual patient. method and device for non-invasive (ni) icp measurement according to inventions of david michaeli md, phd, based to the tra (tissue resonance analysis) have 2 options: (1) the qualitative method makes an evaluation of mild (10-20mm.hg), moderate (20-40) and severe (above 40mmhg) icp elevation. these method is using ni, long-term recording of icp waves patterns, like lundsbergs icp waves. (2) quantitative measurement of icp waves with special icp formulation in mm.hg., developed new device and method for calibration of icp for each patient; see patent description. brain parenchyma more recently, multivariate methods have been proposed that derive icp by combining the transit times with measured acoustic impedance, resonant frequency and ultrasound velocity, or with a dispersion of the ultrasound wave on its way through the brain parenchyma. ultrasound icp monitors based on the latter approach, which were developed at vittamed technologijos (kaunas, lithuania), have shown an impressive agreement with invasively measured icp, with an average difference of only 2–3 mmhg in a small clinical population. however vittamed technologijos time-of-flight technologies were developed further for other applications of neuro-monitoring technologies (including cerebral autoregulation and cerebral compliance). transcranial doppler ultrasonography the tcd measures the velocity of blood flow through the major intracranial vessels by emitting a high frequency (>2mhz) wave from an ultrasound probe and detecting a frequency shift between the incident and reflected wave which directly correlates with the speed of the blood (the so-called doppler effect). the measurement is taken over the regions of the skull with thinner walls (temporal region, back of the head, or through the eye), as the bones strongly attenuate the transmission of the ultrasound at these frequencies. tcd is primarily a technique for diagnosing various intracranial vascular disorders such as emboli, stenosis, or vasospasm, and can be used to identify patients who are at risk of developing cerebral ischemia in early phases of traumatic brain injury or stroke. icp can be estimated from the tcd measurements because it impedes the blood flow and consequently decreases the velocity of blood flow. besides the mean velocity, pulsatility index (which is the difference between peak systolic and end diastolic velocity, divided by mean flow velocity), a fraction of the cycle in systole and slopes of the tcd waveforms have been correlated with icp. the estimates are however insufficiently accurate with the margin of error of ±10 - 15 mmhg. physiosonics, inc. used transcranial doppler ultrasound to measure icp indirectly by assessing the elasticity of the biological material in a defined part of the brain. however, the elasticity in the brain is highly dependent on many other variable individual factors apart from icp, including arterial blood pressure, state of cerebral blood flow auto-regulation, and the level of edema. therefore, this approach would require calibration and expert positioning. skull bones methods from this group attempt to derive icp from mechanical properties of the skull bones rather than of the intracranial content. the underlying assumption is similar to that of the ultrasound time of the flight techniques: that the skull is not completely rigid so that changes in icp result in a small but measurable skull expansion which creates additional stress within the skull bones and modifies their mechanical properties. the transfer function is derived by applying a wide-band, low frequency (<100 hz) mechanical excitation at one location on the skull (via a piezo-transducer or an impact hammer) and comparing its spectrum to that of a signal received at another location on the upper half of skull. it is proposed that the measurement to be self-calibrated by obtaining the frequency response spectrum from a point on the base of the skull of the same subject, which is assumed not to be affected by icp, or alternatively, pre-calibrated on subjects with normal icp. other methods from this group vary this basic approach of mick in different ways. in sinha's method resonant frequency of the skull bones is determined first, then a sinusoidal excitation at the resonant frequency is delivered through a piezo-transducer, and icp is calculated directly from the phase difference between the excitatory signal and response detected with a second transducer. yost