PSEUDOTUMOR CEREBRI Background Pseudotumor cerebri, also known as idiopathic intracranial hypertension (IIH) is a disorder of unknown etiology.

It affects predominantly obese women of childbearing age.[1] The primary problem is chronically elevated intracranial pressure (ICP), and the most important neurologic manifestation ispapilledema, which may lead to progressive optic atrophy and blindness.[1]

Pathophysiology A dominant early theory concerning the pathogenesis of elevated ICP in these patients was cerebral edema. Against this is the fact that no altered level of alertness, cognitive impairment, or focal neurological findings are associated with the elevated ICP. In addition, no pathologic signs of cerebral edema have been documented in these patients. Early reports describing edema were later considered to represent fixation artifact (ie, from tissue preparation) rather than in vivo edema. Current theories include increased resistance to cerebrospinal fluid (CSF) outflow at the arachnoid granulations that line the dural venous sinuses and through which CSF reabsorption is thought to occur by bulk flow. Alternatively, occult cerebral venous outflow abnormalities may produce IIH. Farb and colleagues have demonstrated that, in a series of 29 patients with IIH, narrowing of the transverse dural venous sinus was demonstrable on MR venography, while none of the 59 control subjects had this finding.[2] These authors suggest that the narrowing is a consequence of elevated intracranial pressure, and, when the narrowing develops, it exacerbates the pressure elevation by increasing venous pressure in the superior sagittal sinus.

CSF production rate (mL/min) should be equal to the CSF reabsorption rate. If production exceeds absorption, ICP rises until it exceeds mean arterial pressure, which, if sustained, would be fatal. In IIH the production rate equals the reabsorption rate; however, a higher than normal pressure is required to achieve this owing to the increased resistance at the arachnoid granulations. Bateman has shown that some patients with IIH with normal dural venous drainage have increased arterial inflow suggesting that collateral venous drainage occurs in addition to that provided by the superior sagittal sinus and transverse sinuses.[3] The same investigator measured MR venography and MR flow quantification in cerebral arteries and veins in a series of 40 patients with IIH, of which 21 patients had venous stenosis. The arterial inflow was 21% higher than normal and superior sagittal sinus outflow was normal, resulting in reduced percentage of venous outflow compared to inflow. The remainder of arterial inflow volume is presumed to have drained via collateral venous channels. With clinical remission of symptoms, the arterial inflow volumes returned to normal.[4] More recently, Bateman et al proposed a mathematical model to account for collapsible dural venous sinuses in the pathogenesis of IIH since this has been shown to be an important factor in many cases. The model includes arterial inflow volume, venous outflow resistance, and CSF pressure. They used combined flow rates in the 2 carotid arteries and the basilar artery as measured by MRI in individual patients as the measure of inflow blood volume and measured values from the literature for the pressure gradient from superior sagittal sinus to jugular bulb and venous outflow resistance.

The model predicts 2 CSF pressure equilibrium points for the collapsible dural sinus cases with greater than 40% stenosis (usually of the transverse sinus)one point in the normal range and the other in the range encountered in IIH patients. This accounts for the prolonged remission of symptoms that follows removal of CSF at lumbar puncture, presumably because this relieves the venous sinus stenosis. Without dural sinus collapse and stenosis, as is encountered in some patients with IIH, the model requires increased arterial inflow volume to account for the elevated intracranial pressure. Interestingly, the model did not require increased resistance to outflow of CSF across the arachnoid villi

Causes In 1994, Radhakrishnan et al reviewed the literature on IIH associated with other diseases and with drugs. These authors insisted that, to be included in the list of causally related associations, the following criteria should be met:[11]

At least 2 cases should have been described. The reported cases should have met all the criteria for the diagnosis of IIH. Intracranial dural sinus thrombosis should have been ruled out with reasonable certainty. The following data were obtained from this 1994 study and subsequent case reports. The authors' organization of categories is preserved here Endocrine risk factors confirmed in epidemiological studies Female sex Reproductive age group Menstrual irregularity Obesity Recent weight gain Endocrine risk factors that meet minimal criteria, unconfirmed in case-controlled studies Adrenal insufficiency Cushing disease Hypoparathyroidism Hypothyroidism Excessive thyroxine replacement in children (ie, low thyrotrophin levels) Medication risk factors that meet minimal criteria, unconfirmed in case-controlled studies Cimetidine, corticosteroids, danazol, isotretinoin (Accutane), levothyroxine, lithium,[12] minocycline, nalidixic acid, nitrofurantoin, tamoxifen, tetracycline, trimethoprimsulfamethoxazole[11] All-trans -retinoic acid (ATRA) used in the treatment of promyelocytic leukemia, cyclosporine, levonorgestrel implant (Norplant; 39 women reported to US Food and Drug Administration [FDA] from February 1991-December 1993), pancreatin (pancreatic enzyme replacement for cystic fibrosis patients) Recombinant human growth hormone (7 children in 3 papers)/natural growth hormone (somatotropin) Vitamin A in infants Miscellaneous risk factors that meet minimal criteria, unconfirmed in case-controlled studies Chronic renal failure Systemic lupus erythematosus

NORMAL PRESSURE HYDROCEPHALUS Background Normal pressure hydrocephalus (NPH) is a clinical symptom complex characterized by abnormal gait, urinary incontinence, and dementia. It is an important clinical diagnosis because it is a potentially reversible cause of dementia. First described by Hakim in 1965, NPH describes hydrocephalusin the absence of papilledema and with normal cerebrospinal fluid (CSF) opening pressure on lumbar puncture.[1] Pathophysiology NPH differs from other causes of adult hydrocephalus. An increased subarachnoid space volume does not accompany increased ventricular volume. Clinical symptoms result from distortion of the central portion of the corona radiata by the distended ventricles. This may also lead to interstitial edema of the white matter and impaired blood flow, as suggested in nuclear imaging studies. The periventricular white matter anatomically includes the sacral motor fibers that innervate the legs and the bladder, thus explaining the abnormal gait and incontinence. Compression of the brainstem structures (ie, pedunculopontine nucleus) could also be responsible for gait dysfunction, particularly the freezing of gait that has been well described. Dementia results from distortion of the periventricular limbic system. The term normal pressure hydrocephalus was based on the finding that all 3 patients reported by Hakim and Adams showed low CSF pressures at lumbar puncture, namely 150, 180, and 160 mm H2 O. However, an isolated CSF pressure measurement by lumbar puncture clearly yields a poor estimation of the real intracranial pressure (ICP) in patients with NPH. Hakim first described the mechanism by which a normal or high-normal CSF pressure exerts its effects. Using the equation, Force = Pressure X Area, increased CSF pressure over an enlarged ependymal surface applies considerably more force against the brain than the same pressure in normal-sized ventricles. Normal pressure hydrocephalus may begin with a transient high-pressure hydrocephalus with subsequent ventricular enlargement. With further enlargement of the ventricles, CSF pressure

returns to normal; thus the term NPH, at least in view of the initial pathophysiologic events, is a misnomer. Intermittent intracranial hypertension has been noted in some patients. Some authors prefer the term extraventricular obstructive hydrocephalus. They believe that the initial event is diminished CSF absorption at the arachnoid villi. This obstruction to CSF flow leads to transient high-pressure hydrocephalus with subsequent ventricular enlargement. As the ventricles enlarge, CSF pressure returns to normal. History Patients present with a gradually progressive disorder. As noted above, the classic triad consists of abnormal gait, urinary incontinence, and dementia. The gait disturbance is typically the earliest feature noted and considered to be the most responsive to treatment. The primary feature is thought to resemble an apraxia of gait. True weakness or ataxia is typically not observed. The gait of NPH is characterized as bradykinetic, broad based, magnetic, and shuffling. The urinary symptoms of NPH can present as urinary frequency, urgency, or frank incontinence. While incontinence can result from gait disturbance and dementia, in a study by Sakakibara and colleagues, 95% of patients had urodynamic parameters consistent with detrusor overactivity.[6] The dementia of NPH is characterized by prominent memory loss and bradyphrenia. Frontal and subcortical deficits are particularly pronounced. Such deficits include forgetfulness, decreased attention, inertia, and bradyphrenia. The presence of cortical signs such as aphasia or agnosia should raise suspicion for an alternate pathology such as Alzheimer diseaseor vascular dementia. However, comorbid pathology is not uncommon with advancing age. In one study, more than 60% of patients with iNPH had cerebrovascular disease.[7] In another similar study, more than 75% had Alzheimer disease pathology at the time of shunt surgery.[8] Patients commonly present with a gait disorder and dementia. On neurologic examination, pyramidal tract findings may be present in addition to the above findings. Causes Normal pressure hydrocephalus may occur due to a variety of secondary causes but may be idiopathic in approximately 50% of patients. Secondary

causes of NPH include head injury, subarachnoid hemorrhage, meningitis, and CNS tumor. Another potential cause could be previously compensated congenital hydrocephalus.[9]