Variable Effects of Acetazolamide in Disorders of Cerebral Blood Flow
February 1, 1998
Variable Effects of Acetazolamide in Disorders of Cerebral Blood Flow
ABSTRACTS & COMMENTARY
Sources: Komiyama M, et al. Reversible pontine ischemia caused by acetazolamide challenge. AJNR Am J Neuroradiol 1997;18:1782-1784; Sakashita Y, et al. Changes in cerebral blood flow and vasoreactivity in response to acetazolamide in patients with transient global amnesia (TGA). J Neurol Neurosurg Psychiatry 1997;63:605-610.
Sakashita et al describe semi-quantitative SPECT changes in regional cerebral blood flow (CBF) in six patients aged 56-63 years with transient global amnesia (TGA). Two were studied early during an attack, and one was evaluated five hours after TGA ended. The other three were evaluated 6-10 hours after the end of the attack. Resting CBF values were obtained using the Tc HMPAO SPECT technique, followed immediately afterward by administration of 1 g acetazolamide, repeated 15 minutes later. Repeat Tc HMPAO SPECT procedure was then performed. A 10% change in focal CBF was considered significant.
Three patients analyzed early (two during an attack, one five hours after its end) showed resting increases in CBF in occipital cortex and cerebellum. Two of the three also had increased flow in frontal, temporal, and parietal cortices. In the other three patients, resting CBF obtained from 20 to 23 hours after the attack showed modestly decreased areas of CBF, one in the putamens, one unilaterally in the thalamus as well as bilaterally in the cerebellum, and the third in bitemporal cortices, as well as in unilateral hippocampal-parahippocampal regions. In the three early studied patients with areas showing increased areas of resting CBF, acetazolamide induced no further increase in the hyperemic regions. The other three patients tested at 6-10 hours post TGA showed increased CBF following acetazolamide, as did all six patients 25-35 days after the TGA attack.
Relevant to Sakashita et al’s study, Komiyama et al describe the effects of acetazolamide on a diabetic, hypertensive, 48-year-old man who, for a month, had suffered episodic basilar artery-induced TIAs. Attacks included feelings of dysequilibrium and left hemicorporeal numbness, leaving no residual abnormalities. A final sustained attack added sustained left-sided hemiparesis to the above. MRI showed a right pontine infarct, and angiography identified basilar artery stenosis at the mid pontine level. Functional SPECT showed CBF of 62.4 mL/100 g/min at the pontine level of the basilar artery, whereas left middle carotid artery (LMCA) flow was 60 mL/100 g/min. Five days later, 1 g of acetazolamide was injected IV followed by functional SPECT. One minute later, the patient experienced circumoral paresthesias (not a rare experience) plus a left hemiparetic numbness (not an unexpected event), accompanied by increased left hemiparesis, dysarthria, and gait difficulties. LMCA blood flow measured 74 mL/100 g/min, whereas flow in the basis pontis dropped to 55 mL/100 g/min. The patient’s numbness disappeared in about four hours, but the other new symptoms lasted for 3-4 days. Subsequent MRI showed no change in the pontine infarct.
COMMENTARY
Attacks of TGA are well known to include a relatively consistent syndrome of an abrupt onset of remote memory loss with preservation of immediate memory as well as remotely learned motor and behavioral skills. Only nine SPECT or PET blood flow studies during an attack are available in the literature, including the Sakashita study. Among these, five show increased CBF.
Sakashita et al’s data indicate that during the symptomatic expression of TGA, CBF can increase in some brain areas but not in others. Acetazolamide injection had no influence on these changes. By 6-10 hours or more after the attack, CBF in all patients was subnormal and acetazolamide sensitive. The observations, at the least, suggest that TGA attacks are not simply due to cerebralarterial ischemia.
A number of clinical observers have suggested that acetazolamide may be useful in dilating cerebral arteries in symptomatic patients with acute ischemic intracranial disease. Komiyama et al emphasize the danger of such an approach. Acetazolamide is a complicated drug. It is an amide derivative belonging to the sulfonamide family and best known for its capacity to inhibit carbonic anhydrase, thus reducing HCO3- in tissues, including the brain. The resulting increase in PCO2 generates an increase in tissue PCO2 tensions with an accompanying pH reduction believed to dilate cerebral blood vessels. Unfortunately, aside from its value in reducing ocular HCO3- production in patients with open-angle glaucoma and its small capacity as an anticonvulsant, acetazolamide tends to impair rather than improve cerebral functional activity. Thus, Posner and Plum (J Clin Invest 1960;39:1246-1258) found that the drug worsens hepatic encephalopathy. Other subsequent studies have suggested its toxic effects are a result of a systemic metabolic acidosis plus increasing renal ammonia retention.
The results of the two index papers both suggest reason for not using acetazolamide in the presence of potential cerebral vascular insufficiency. Alert recommends avoiding the use of acetazolamide to treat patients with migraine, TGA, or brain acute ischemic attacks. No evidence suggests a value for the agent in these circumstances. Worse is that vascular flow at the locus of damage may already be dilated by local stimuli and can only either maintain steady state or decline if cerebral blood flow shunts to dilated arteries of other areas of the brain. fp
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