Management of Intracranial Stenotic Disease in Cancer Patients Treated With Vasotoxic Agents.

OBJECTIVE: To summarize the characteristics of and therapeutic options for cancer patients whose treatments may be vasotoxic and cause intracranial arterial stenotic disease and stroke. METHODS: We describe 3 patients with symptomatic cerebrovascular pathology that were being actively treated for cancer. RESULTS: Two of the patients were being treated with tyrosine kinase inhibitors (TKIs); and the third was being treated with 2 monoclonal antibodies, one of which was targeting an endothelial growth factor. These agents have been associated with vascular adverse events. Surgical revascularization was done in the first 2 patients, as they were suffering from cerebral ischemia. The third patient had suffered a significant brain hemorrhage, and therapeutic options were limited. In the first 2 patients, treatments also included antiplatelet agents and stopping/changing the TKI. In one of these patients we demonstrated regression of arterial stenosis after changing the TKI. CONCLUSIONS: Possibilities for treatment in this population, beyond the usual medical and surgical administrations, may include stopping or changing cancer drugs that may be related to the development of arterial pathology. Collaboration with oncologists is essential in this subset of patients. While aware of the potential for vascular toxicity, oncologists are often not fully appreciative of the fact that their therapeutic agents can cause stroke.

Reversible Cerebral Vasoconstriction Syndrome after Administering Etanercept during Puerperium.

Our objective is to clarify relationship between reversible cerebral vasoconstriction syndrome and administrating etanercept during puerperium. Several lines of evidence have suggested tumor necrosis factor (TNF) as a mediator of vascular dysfunction associated with estrogen deficiency. A 32-year-old woman resumed etanercept (25 mg/week), a TNF inhibitor, which had been discontinued during pregnancy, because of the deterioration of rheumatoid arthritis. She was admitted to our hospital with upper right quadrant blindness and mild right hemiparesis accompanied by pulsating left occipital pain, which had appeared 4 hours after restarting etanercept (25 mg/week). Magnetic resonance imaging and angiography revealed acute left hippocampal infarction with multiple segmental stenoses of the main intracranial arteries. Reversible cerebral vasoconstriction syndrome was diagnosed based on improvement of the multiple stenoses on magnetic resonance angiography on hospital day 17. A causal relationship was considered to exist between TNF inhibition by etanercept and multiple cerebral vasoconstrictions with brain infarct in this puerperant.

Frequency and Risk Factors for Cerebral Arterial Disease in a HIV/AIDS Neuroimaging Cohort.

BACKGROUND: Infection with HIV predisposes patients to a myriad of neurologic disorders, including cerebrovascular disease. The pathophysiology is likely multifactorial, with proposed mechanisms including infectious vasculitis, HIV-induced endothelial dysfunction and adverse effects of combination antiretroviral therapy (cART). Epidemiologic data on clinically evident cerebral vasculopathy in HIV-infected adults is scarce, even though stroke hospitalizations are rising in this patient population. METHODS: A total of 6,298 HIV-infected adults (San Francisco General Hospital, 2000-2013) were screened to generate a cohort of patients with dedicated neuroimaging of the intra- and extracranial cerebral vasculature. We extracted information regarding the extent of HIV disease (including serial viral load and CD4 counts), cardiovascular disease risk factors and exposure to cART (cross-referenced with pharmacy records) and performed multivariate logistic regression analysis to identify predictors of vasculopathy. RESULTS: Of 144 patients, 55 patients (38.2%) had radiographic evidence of cerebral vasculopathy. Twenty (13.9%) had a vasculopathy characterized by vessel dolichoectasia and intracranial aneurysm formation. Thirty-five patients (24.3%) had intra- and or extracranial stenosis/occlusion. cART use (OR 2.27, 95% CI 1.03-5) and tobacco abuse (OR 2.35, 95% CI 1.04-5.25) were independently associated with the development of any vasculopathy, whereas cART use was also an independent risk factor for the stenosis/occlusion subtype specifically (OR 2.87, 95% CI 1.11-7.45). CONCLUSIONS: There was a high frequency of cerebral arterial disease in this neuroimaging cohort of HIV/AIDS patients. A history of cART use and a history of tobacco abuse were independent risk factors for vasculopathy, though these findings should be confirmed with large-scale prospective studies.

Angiotensin-(1-7) and low-dose angiotensin II infusion reverse salt-induced endothelial dysfunction via different mechanisms in rat middle cerebral arteries.

The goals of this study were to 1) determine the acute effect of ANG-(1-7) on vascular tone in isolated middle cerebral arteries (MCAs) from Sprague-Dawley rats fed a normal salt (NS; 0.4% NaCl) diet, 2) evaluate the ability of chronic intravenous infusion of ANG-(1-7) (4 ng·kg(-1)·min(-1)) for 3 days to restore endothelium-dependent dilation to acetylcholine (ACh) in rats fed a high-salt (HS; 4% NaCl) diet, and 3) determine whether the amelioration of endothelial dysfunction by ANG-(1-7) infusion in rats fed a HS diet is different from the protective effect of low-dose ANG II infusion in salt-fed rats. MCAs from rats fed a NS diet dilated in response to exogenous ANG-(1-7) (10(-10)-10(-5) M). Chronic ANG-(1-7) infusion significantly reduced vascular superoxide levels and restored the nitric oxide-dependent dilation to ACh (10(-10)-10(-5) M) that was lost in MCAs of rats fed a HS diet. Acute vasodilation to ANG-(1-7) and the restoration of ACh-induced dilation by chronic ANG-(1-7) infusion in rats fed a HS diet were blocked by the Mas receptor antagonist [D-ALA(7)]-ANG-(1-7) or the ANG II type 2 receptor antagonist PD-123319 and unaffected by ANG II type 1 receptor blockade with losartan. The restoration of ACh-induced dilation in MCAs of HS-fed rats by chronic intravenous infusion of ANG II (5 ng·kg(-1)·min(-1)) was blocked by losartan and unaffected by d-ALA. These findings demonstrate that circulating ANG-(1-7), working via the Mas receptor, restores endothelium-dependent vasodilation in cerebral resistance arteries of animals fed a HS diet via mechanisms distinct from those activated by low-dose ANG II infusion.

Moyamoya in a child treated with interferon for recurrent osteosarcoma.

SUMMARY: Moyamoya is a cerebral vasculopathy of unknown etiology rarely described as a late effect after the treatment of childhood cancer. We describe a 12-year-old female who developed moyamoya after the completion of systemic chemotherapy, surgery, and adjuvant interferon alpha for osteosarcoma with pulmonary metastases. Given the importance of characterizing late effects after the treatment of childhood cancer, the potential role of interferon alpha in the development of moyamoya is discussed.

Dihydrotestosterone stimulates cerebrovascular inflammation through NFkappaB, modulating contractile function.

Our previous studies show that long-term testosterone treatment augments vascular tone under physiological conditions and exacerbates endotoxin-induced inflammation in the cerebral circulation. However, testosterone can be metabolized by aromatase to estrogen, evoking a balance between androgenic and estrogenic effects. Therefore, we investigated the effect of the nonaromatizable androgen receptor agonist, dihydrotestosterone (DHT), on the inflammatory nuclear factor-kappaB (NFkappaB) pathway in cerebral blood vessels. Cerebral arteries were isolated from orchiectomized male rats treated chronically with DHT in vivo. Alternatively, pial arteries were isolated from orchiectomized males and were exposed ex vivo to DHT or vehicle in culture medium. DHT treatment, in vivo or ex vivo, increased nuclear NFkappaB activation in cerebral arteries and increased levels of the proinflammatory products of NFkappaB activation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Effects of DHT on COX-2 and iNOS were attenuated by flutamide. In isolated pressurized middle cerebral arteries from DHT-treated rats, constrictions to the selective COX-2 inhibitor NS398 or the selective iNOS inhibitor L-nil, [L-N6-(Iminoethyl)lysine], were increased, confirming a functional consequence of DHT exposure. In conclusion, activation of the NFkappaB-mediated COX-2/iNOS pathway by the selective androgen receptor agonist, DHT, results in a state of vascular inflammation. This effect may contribute to sex-related differences in cerebrovascular pathophysiology.

Gamma-Hydroxybutyrate (GHB), gamma-butyrolactone (GBL), and 1,4-butanediol (1,4-BD) reduce the volume of cerebral infarction in rodent transient middle cerebral artery occlusion.

gamma-Hydroxybutyric acid (GHB), an endogenous organic acid catabolite of gamma-aminobutyric acid (GABA), has been shown to have tissue-protective effects in various organs, including the brain. We examined the potential neuroprotective effect of GHB and its chemical precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), in the rodent ischemic stroke model by intraluminal filament middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats underwent transient left-sided MCAO and received intraperitoneal treatment with 300 mg/kg of GHB, GBL, 1,4-BD, or control vehicle given at 30 min before, as well as 180 and 360 min after the onset of ischemia. Infarct volumes were determined 24 h after MCAO. In transient MCAO, the mean volume of infarction for control rats was 464.4 +/- 17.9 cu.mm versus 273.6 +/- 53.1, 233.3 +/- 44.7, and 275.4 +/- 39.9 cu.mm for rats treated with 1,4-BD (P < 0.05), GBL (P < 0.05), and GHB (P < 0.05), respectively. We conclude that GHB, GBL, and 1,4-BD protect against rat focal cerebral ischemia from transient MCAO.

[Reversible postpartum cerebral angiopathy associated with bromocriptine therapy]. / Angiopathie cérébrale réversible du post-partum imputable à la bromocriptine.

BACKGROUND: Postpartum is known to be an important risk factor for stroke. Bromocriptine may induce cerebral angiopathy. CASE DESCRIPTION: We report the case of a 26-year-old postpartum woman who presented with headaches, seizures, hypertension and acute renal failure eight days after the beginning of a treatment with bromocriptine prescribed for lactation suppression. Brain MRI and MR angiogram excluded cortical vein thrombosis and revealed multiple abnormal areas of increased signal in the cortex with segmental arterial narrowings of intracranial vasculitis. The patient completely recovered within one week after drug withdrawal. Biological and radiological abnormalities were also reversible. Following the chronology bromocriptine was most likely responsible for this adverse cerebral and systemic event. CONCLUSION: Clinicians should be aware of bromocripine-related postpartum cerebral angiopathy, a rarely described but serious complication of bromocriptine used to prevent postpartum breast engorgement.

Cerebral arteritis following methylphenidate use.

Stroke is a well-documented complication of amphetamine abuse. Methylphenidate, chemically and pharmacologically similar to amphetamines, is widely used in the treatment of attention deficit disorder in children. The possibility of vasculitis connected to methylphenidate should not be surprising. A case is reported of stroke associated with ingestion of methylphenidate in an 8-year-old boy. Family history was negative and other causes of vasculitis were excluded. We draw your attention to the risk of using methylphenidate for a long period of time.

[Neurologic toxicity of methotrexate in a patient with cerebral arteritis. Report of a case]. / Toxicité neurologique du méthotrexate avec artérite cérébrale. Un cas.

We report the case of an 18 year-old woman treated for femoral osteogenic sarcoma who presented generalized seizures requiring sedation, tracheal intubation and artificial ventilation. CT brain scan showed diffuse hypodensities. Doppler studies showed an increased cerebral arterial resistance. Regional cerebral blood flow was decreased. A right carotid angiogram showed abnormalities consistent with diffuse cerebral arteritis. The patient slowly recovered and 6 weeks later, magnetic resonance imaging showed disseminated areas of hyposignal on T1 and hypersignal on T2 weighted images. We reviewed the different published cases of acute high dose methotrexate neurotoxicity and the different underlying mechanisms.

[Postpartum cerebral angiopathy of iatrogenic origin]. / Angiopathie cérébrale du post-partum d'origine iatrogène.

A 30 year old women, beginning her 19th day postpartum, was admitted for lowering of alertness. The day before she complained of cephalalagia. Neurologic examination showed pyramidal tract signs on the right part of the body, a bilateral Babinski sign, and central oculomotor palsy. She started a treatment by nasal pulverization of phenylephrine, a sympathomimetic vasoconstrictor, one week before, and took bromocriptine (5 mg per day) from childbirth to second week postpartum. CT scan was normal. Lumbar puncture showed a high level of proteins, from transsudative origin. Cerebral angiography showed a beading aspect of arterial branches, especially in the left middle cerebral artery territory. Two days after drug withdrawal, the patient recovered. This angiographic pattern has already been described in cases of cerebral angiopathy due to sympathomimetic drug abuse, and in cases of postpartum cerebral angiopathy. The chronology, in our case, makes the responsibility of the phenylephrine very likely. Nonetheless, ergot derivatives (i.e. ergonovine, bromocriptine) have also been accused of giving cerebral postpartum angiopathy. In our case, we think that bromocriptine may have triggered the cerebral angiopathy due to phenylephrine.

Cerebral arteritis associated with oral use of phenylpropanolamine: report of a case.

Phenylpropanolamine (PPA) is the major ingredient of many over-the-counter cold remedies and diet pills. Use or abuse of PPA may cause hemorrhagic stroke or cerebral vasculitis similar to the clinical and angiographic picture associated with amphetamine use or abuse. We report a 32-year-old Taiwanese women who developed sudden onset of severe headache, nausea and vomiting on the seventh day of oral ingestion of 75 mg PPA per day. Cerebral angiograms showed multiple areas of alternating focal constriction and dilatation ("beading" appearance) in the anterior and posterior cerebral arteries consistent with cerebral arteritis. This case should alert medical practitioners to the potential hazards of over-the-counter drugs like PPA.

Contrast-enhanced MR of cerebral arteritis: intravascular enhancement related to flow stasis within areas of focal arterial ectasia.

The authors present a case of probable amphetamine-induced cerebral arteritis in a 31-year-old man with AIDS, testicular carcinoma, and recurrent pneumocystis pneumonia. MR enhancement was demonstrated in areas of focal arterial ectasia, presumably due to slow flow. CT, MR, and angiographic findings were strikingly confirmed postmortem. Angiography remains essential in the diagnosis of cerebral arteritis.

[On the mechanism underlying spasmogenic actions of oxy-hemoglobin on the cerebral artery, analyzed from the inhibitory effects of nicardipine, procaine and indomethacin].

The present study was to analyze the basic mechanism underlying spasmogenic actions of Oxy-hemoglobin (Oxy-Hb) on the bovine cerebral arteries. Using helical strips of the middle cerebral arteries (M2), the changes in muscular tension during an isometric contraction induced by either Oxy-Hb, hydrogen peroxide (H2O2), high potassium-ion-Tyrode (30 mM K+), prostaglandin F2 alpha (PGF2 alpha), or carbocyclic thromboxane A2 (cTXA2) were recorded on the polygraph. Blocking effects of nicardipine, procaine indomethacin were compared on the contractions produced by each reagent described above. The results obtained are summarized as follows. 1) H2O2 dissolved in different concentrations produced arterial contractions similar to those by equimolar Oxy-Hb, showing similar dose-response curves. In contrast, equimolar met-hemoglobin (Met-Hb) always produced much weaker contractions. When the equimolar H2O2 was applied during an Oxy-Hb-induced contraction, the response to H2O2 was completely occluded. When H2O2 was applied during a Met-Hb-induced contraction, the response to H2O2 was not occluded and always additive to the response to Met-Hb. Indomethacin blocked both responses to Oxy-Hb and H2O2, showing similar dose dependence. 2) The above results suggested that Oxy-Hb induced contraction consisted of two components; a strong contraction by active oxygen within Hb molecule, and a weak contraction by Hb molecule itself. The former may be mediated by some PG's which are produced inside the muscle cells as the results of arachidonic acid release and subsequent cyclooxygenase activation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Benign cerebral angiopathies and phenylpropanolamine]. / Angiopathies cérébrales bénignes et phénylpropanolamine.

Heroin, cocaine, amphetamines, sympathomimetic drugs can cause cerebral angiopathy. We report 2 patients with cerebrovascular disorders after ingestion of a nasal vasoconstrictor containing phenylpropanolamine (P.P.A.). The first patient had two acute repetitive attacks of severe headache and vomiting, occurring after a daily treatment with 180 mg of P.P.A. during 6 weeks. The second patient had an intracerebral hemorrhage, occurring some hours after taking for the first time 120 mg of P.P.A. In both cases, cerebral angiography, performed in the next week, demonstrated segmental narrowing and dilatations of medium-size intracranial arteries. None of the usual causes of cerebral vasculitis were present. The outcome was favorable and follow-up angiograms showed the disappearance of the beading pattern. P.P.A. is widely used over the counter in diet pills and stimulants. Cerebral vascular complications have been rarely reported, always hemorrhagic and often associated with cerebral vasculitis. They are unrelated to duration or dosage of treatment. The mechanism is unclear but could result from several factors: chronic or paroxystic high blood pressure, immuno-allergic vasculitis, arterial spasm, direct "toxic" effect of the P.P.A. on the arterial wall may be increased by other drugs and caffeine.

Cerebral vasculitis associated with cocaine abuse.

A case of cerebral vasculitis in a previously healthy 22-year-old man with a history of cocaine abuse is described. Cerebral angiograms showed evidence of vasculitis. A search for possible causes other than cocaine produced no results. We now include cocaine with methamphetamines, heroin, and ephedrine as illicit drugs that can cause cerebral vasculitis.

Unusual vascular events in the territory of the posterior cerebral artery.

There is an unusual type of vascular episode in the territory of the posterior cerebral artery which remains relatively unknown. Ten cases are presented in which a posterior cerebral artery deficit developed suddenly in dramatic fashion with headache, visual symptoms, sensory and motor deficits and signs of third nerve involvement. Nine of the patients were female and one was male. Seven were under the age of 33. In all instances there was a permanent neurologic sequela, usually a hemianopia. A similar case was described in 1901. The nature of the underlying process remains obscure, but the evidence favors accompanied migraine in which a particularly severe attack results in permanent damage. The term "catastrophic migraine" is suggested.

PIP: 10 cases are presented in which a posterior cerebral artery (PCA) deficit developed suddenly in dramatic fashion with headache, visual symptoms, sensory and motor deficits, and signs of 3rd nerve involvement. There were 9 females and 1 male, ranging in age from 18-51 years with 7 cases under age 35. In 9 of the 10 patients, headache was prominent at the onset; 6 patients reported being dramatically stricken with a severe, sharp localized pain in the forehead or occiput. Visual symptoms were prominent at the onset in 7 patients -- 4 patients experiencing blindness and 3 patients a hemianoptic deficit. Hemisensory symptoms or deficit occurred in 6 instances, a hemiparesis in 3, combined weakness and sensory deficit in 1. Evidence of a 3rd nerve palsy was found in 3 cases. A persisting neurologic deficit occurred in 10 cases -- visual field defect, 6 cases; hemiplegia, 1; slight weakness, 1; and a sensory deficit, 2. A movement disorder developed on the involved side in 7 cases. Evidence of infarction in 1 or both occipital lobes was obtained in 6 patients. 1 patient did not have impaired visual fields, and the other 3 were examined before the days of nuclear medicine and CT scanning. Conventional angiography was performed in 8 patients with the following results: retrothalamic occlusion of 1 PCA (1 patient); distal occlusion of 1 PCA (1 patient); retrothalamic narrowing of 1 PCA (1 patient); irregularity of the wall of the upper basilar artery and both PCAs (1 patient); and in 4 angiography was normal. A digital subtraction angiogram in 1 patient was normal; 1 patient did not have an arteriogram. A history of accompanied migraine was obtained in 3 patients. 1 patient was pregnant; 1 patient was 3 months postpartum. 1 patient was taking oral contraceptives; 1 patient had taken 1 contraceptive pill, and 1 patient was receiving injections of estrogen. These cases represent involvement of the territory of the PCA. They share the same features in varied combinations. The onset or evolution is dramatic, distinctive, or alarming. The cases do not fall easily into any commonly recognized category of cerebrovascular disturbances. The process that most likely applies to this group of cases is migraine. If that is so, the term "catastropic migraine" or "cataclysmic migraine" may have some currency. If it is assumed that the process is ischemic and since vascular obstruction was found in 2 cases, the possibility of using heparin therapy might be considered. In most of the present cases, steroid therapy was used to control brain swelling. If the pathologic process is temporary vasospasm, the use of hemodilution or hyperbaric oxygen could be an option.