The diagnosis of PTC based on the Modified Dandy Criteria
The diagnosis of PTC, based on the Modified Dandy Criteria, is made when a patient exhibits an elevated LP opening pressure above 25cm H20 with normal CSF composition and radiologic findings, and no other explanation for the rise in intracranial pressure . The most common presenting symptom occurring in nearly all patients is headache. Other signs and symptoms known to occur to a lesser degree include nausea, vomiting, transient visual disturbances, diplopia, papilledema, and pulsatile tinnitus. Symptoms usually develop within 14 days of ATRA initiation . In our practice, patients receiving ATRA who report persistent headache that is poorly controlled with opiates or other commonly used analgesics typically undergo a LP to investigate the possibility of PTC. The LP is usually considered after more than 24h of symptoms, or sooner if the patient reports visual disturbance in addition to headache. Of the five cases of PTC presented in this report, three cases developed symptoms following their very first dose of ATRA. However, in two patients, development of PTC was delayed (see Table 1), highlighting that PTC can occur at any point during therapy. PTC secondary to ATRA administration for APL has been well described in the literature through case reports in both the pediatric and young adult populations [7–26] and, among adults, has been most often associated with obese women of child-bearing age . However, all patients described in this report were males with a wide age range and body mass indexes (BMIs) consistent with an overweight (BMI 25.0–29.9kg/m2) or obese (BMI≥30kg/m2) stature. Given the remarkable incidence of PTC in our patients receiving ATO-ATRA, it is possible that ATO may foster the development of this condition in APL patients. PTC has been reported previously in a 21-year old woman receiving ATO consolidation therapy for APL without concurrent ATRA . The mechanism for ATO induced PTC has not been identified. However, the primary mechanisms of agents known to cause PTC involves the alteration of CSF Sephin 1 Supplier by effects on either the pressure differential between the central nervous system and venous blood (increasing inflow), or the arachnoid villi (reducing outflow) . The suggested mechanism of ATRA induced PTC is a toxic pathophysiological interaction between vitamin A derivatives and lipid constituents of the choroid plexus and arachnoid villi, resulting in inhibited CSF absorption and an increase in intracranial pressure . Treatment of this condition is necessary to prevent the primary complication, blindness, secondary to progressive optic disc swelling and atrophy . Management strategies aim to lower intracranial pressure through one or more of the following: removal of the offending agent (discontinuation of ATRA), removal of CSF (therapeutic LPs), inhibition of CSF production (acetazolamide), diuresis (mannitol, glycerin, furosemide), and analgesia. Topiramate has more recently been described as a treatment option for PTC . This agent is primarily used in the management of epilepsy, but is also indicated for migraine prophylaxis . Migraine headaches share similar pathophysiological mechanisms with seizures, including abnormal function of voltage-gated sodium and calcium channels, reduced GABA mediated inhibition, and increased glutamate-mediated excitation, many of which may be antagonized by topiramate [30,39]. It is unclear why topiramate was effective after the failure of acetazolamide in our patient population. Our patients received a maximum of 1g of acetazolamide daily (administered as 500mg twice daily). The optimal dose of acetazolamide for management of PTC is unknown, however a recent publication in patients with idiopathic PTC administered an initial total daily dose of 1g and titrated up weekly as tolerated to a maximum daily dose of 4 grams . It is unclear if our patients would have had better symptom control on higher doses of acetazolamide. We did not repeat LPs to assess the actual reduction in opening pressure after initiation of topiramate. Given that ATRA may cause headache even in the absence of ICP changes, it is possible that topiramate is simply better at managing such drug induced headache than acetazolamide is, and that it is not necessarily any better at decreasing ICP. Such a theory may be supported by the efficacy of topiramate in managing migraine headache. It is also possible that the additional mechanisms of action of topiramate, as compared to acetazolamide, may have played a role in further reducing intracranial pressure lower than that able to be obtained with acetazolamide alone, thus resulting in improved symptom control.