Is Normal Pressure Hydrocephalus A Component of Multiple Sclerosis Pathology?
Normal venous hydrocephalus (NPH) is characterized by non-obstructive enlargement of the lateral ventricles, and sometimes the third ventricle, in combination with one or more of the following symptoms (known as Hakim’s Triad): gait disturbance, urinary dysfunction and/or cognitive dysfunction (Tsakanikas and Relkin, 2007, Wallenstein and McKhann, 2010). These symptoms may vary in severity from undetectable through mild to severe. Features of NPH gait disturbance include “slow, short steps with reduced foot-floor clearance…” (Tsakanikas and Relkin, 2007), this is similar to what is seen even in mildly impaired multiple sclerosis (MS) patients (Benedetti et al., 1999). Cognitive impairment includes “slowing of information processing, memory and executive function abnormalities, psychomotor slowing…” (Tsakanikas and Relkin, 2007), similar to what can be seen in some people with MS (Gil Moreno et al., 2013). Urinary disturbances include urinary urgency and in severer cases, incontinence (Tsakanikas and Relkin, 2007), both of which are common in people with MS (Murphy et al., 2012). People with MS also exhibit enlarged ventricles (Martola et al., 2008).
The cause of most cases of NPH is unknown. Idiopathic NPH becomes more common with age: in a Norwegian population the overall population prevalence is 22/100,000 but in the population aged 70 to 79 the prevalence is 182/100,000 (Brean and Eide, 2008). How NPH results in Hakim’s Triad is not known. A possible clue may be present in another brain-related feature that becomes more common with aging: this is a reduction in intra-cranial compliance (Stoquart-ElSankari et al., 2007). The cranium is essentially a closed box filled with either incompressible tissues or incompressible fluids. During systole the increase in the volume of the arteries within the cranial cavity results in pressure applied to the cerebrospinal fluid (CSF) within the subarachnoid space and to the venous structures. An immediate consequence of the pressure applied to the CSF is movement of CSF from the cranial subarachnoid space to the spinal subarachnoid space: this is allowed because of the elasticity of the spinal arachnoid mater, particularly in the lumbosacral region. In addition, the pulse pressure transmitted from the arteries to the CSF results in pressure transmitted via the dura mater onto the dural venous sinuses as well as onto the brain parenchyma causing partial collapse of the veins: this results in the movement of venous blood to extra-cranial pathways. Pressure is also applied by the CSF to the brain tissues and dural venous sinuses because of the elastic rebound of the lumbosacral arachnoid mater during diastole when the arteries are undergoing an elastic rebound. The dampening of the pulse pressure (Windkessel effect) is initiated in the larger arteries as they pass from the dura mater traversing the subarachnoid space to the pia mater before they penetrate brain parenchyma. Because of dissipation of some of the pulse pressure by the CSF, the pulse pressure of the parenchymal arteries would be less and the Windkessel effect would be mainly mediated by partial collapse of the parenchymal veins with only a small amount of the pulse pressure normally transmitted to the arteries of the choroid plexus (Egnor et al., 2002).
If the volume of CSF increases, as seems to be the case with NPH, then because of the stretching of the lumbosacral arachnoid mater there is less ability of the spinal subarachnoid space to accommodate the CSF movement during the increased arterial volume during systole, i.e., there is less compliance. This has been demonstrated experimentally (Kim et al., 2010). A consequence of less compliance is that blood flow through the arterioles, capillaries and post capillary venules would have a more pulsatile rather than a smooth laminar flow characteristic since more of the force exerted by the heart during systole is transmitted to blood flow rather than the elastic expansion of the intracranial arteries (Egnor et al., 2002). It is the increased pulsatility of the choroid plexus arteries and associated pulsation of ventricular CSF that is responsible for ventricular enlargement in NPH (Egnor et al., 2002, Graff-Radford et al., 2013). Hakim’s Triad may be a consequence of a pulse wave encephalopathy, a term coined by Bateman (Bateman, 2002).
Is there any evidence that increased pulsatility of the arteries of the choroid plexus is also responsible for increased ventricular size in MS? I am not aware of any laboratory that has looked into this. I will, therefore, start with the question whether there is evidence for decreased intracranial compliance in MS? A number of studies have demonstrated reduced CSF flow in response to arterial volume changes (Zamboni et al., 2010, Magnano et al., 2012), all suggestive of decreased intracranial compliance. Another study has demonstrated that intracranial compliance increases following angioplasty to correct for obstructed venous return in people with MS (Zivadinov et al., 2013). Decreased compliance should also result in increased intravenous pressure (Egnor et al. 2002). I could find only two laboratories that addressed this question: one found no increased intravenous pressure when measured indirectly using ophthalmodynamometry (Meyer-Schwickerath et al., 2011)and the other demonstrated an increase in venous pressure from 1.3 to 3 mm Hg when measuring the pressure upstream of a stenosis compared to downstream of a stenosis in MS patients (Zamboni et al., 2009a, Zamboni et al., 2009b). A small increase in venous pressure certainly will affect the small differential of pressures (normally 1-3 mm Hg) between the CSF of the subarachnoid space and the superior sagittal sinus, thereby increasing the total volume of CSF. Increase in CSF volume will result in less intracranial compliance since the stretched arachnoid mater would be less compliant. Early increases in CSF volume, because of the elasticity of the arachnoid mater, would not cause an increase in intracranial pressure beyond what is considered normal (7-15 mm Hg).
A decrease in arachnoid mater compliance and increase in venous pressure should also increase the pulsatility of the intracranial veins (Bateman et al., 2008). A recent study comparing the hemodynamics of a pediatric population with MS to an age-matched control population demonstrated a significantly increased pulsatility of the epidural veins of the MS population compared to the healthy controls (Macgowan et al., 2013). Intracranial venous pulsatility was not examined; however, the spinal epidural veins are homologous to the dural venous sinuses within the cranial cavity and, possibly, reflect what is occurring intracranially. Although the authors conclude that there are no hemodynamic differences between the two populations they did point out a non-significant trend towards a lower blood flow in left internal jugular vein in the MS population.
Finally, periventricular white matter lesions are common in NPH (Krauss et al., 1997), as they are in multiple sclerosis.
Concluding Comments: Both NPH and MS are characterized by non-obstructive enlargement of the ventricles and by Hakim’s Triad. I believe there is sufficient evidence to seriously consider the possibility that NPH plays a role in the pathological mechanisms involved in MS. Research from this perspective is warranted. If future research provides additional evidence that NPH is part of the MS pathology (e.g., demonstration of greater pulsatility of intracranial veins) this may well offer new avenues for treatment.
Note, I am not arguing that NPH causes MS, simply that it may be one of the mechanism involved in MS pathology. Nor am I making an argument that obstructed veins play a role in the pathology in MS, although this may be the case, at least in some individuals: it is interesting that many people who have MS, diagnosed with obstructed veins and who have undergone angioplasty report the disappearance of “brain fog”, improved locomotory ability and regain of proper bladder function, i.e., improvements in functions of what has been labeled Hakim’s Triad, defining features of NPH.
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