cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( cadasil ) [ mim 125310 ] is an autosomal dominant microangiopathy caused by mutations of the notch3 gene that is located on chromosome 19 and encodes a transmembrane receptor . the clinical spectrum of the disease includes migraine with and without aura , early onset cerebrovascular events , mood disturbances , apathy , cognitive impairment and , more rarely , epilepsy [ 1 , 2 ] . the typical neuroimaging findings on magnetic resonance imaging ( mri ) consist of multifocal and bilateral flair / t2-weighted hyperintensities in the white matter , often involving the anterior temporal poles and the external capsules . focal hypointensities on t1 ( evidence of lacunar infarcts ) and lesions suggestive of microhemorrhages in gradient echo images are also seen [ 3 , 4 ] . migraine is frequently the presenting disturbance of the disease , developing in many patients in the second or third decades of life . in cadasil , migraine with aura is particularly common and a large proportion of patients experience atypical patterns of aura such as aura without headache , basilar and hemiplegic migraine , and attacks of prolonged aura . recently , cases of persistent aura , status migrainous   and acute confusional migraine   have also been described in cadasil patients . despite migraine is not the most disabling disturbance of cadasil , it may cause persistent discomfort to patients , especially in those with frequent attacks , and may lead to hospitalization , especially because some auras are difficult to differentiate from cerebrovascular events in these patients . in cadasil , the coexistent of migraine , cerebrovascular events , and microangiopathy is also a point of interest as far as pathogenesis is concerned . there have been anecdotic reports on the efficacy of acetazolamide as a treatment of migraine in cadasil [ 8 , 9 ] , but no further study has explored this aspect . we have thus retrospectively reviewed our database of cadasil patients to assess how many of them had been treated with acetazolamide for migraine and the efficacy and tolerability of this therapy . for the purpose of our survey , we retrospectively reviewed our database of patients with a genetic diagnosis of cadasil . the efficacy and the tolerability of acetazolamide treatment were checked looking at the clinic reports . to assess the success of acetazolamide treatment , we evaluated the number and the quality of migraine attacks after starting this prophylactic treatment . we classified as with  significant improvement  all patients in whom no further attack was recorded at subsequent visits and with  improvement  those in whom there was a reduction in intensity and/or frequency of attack , but some disturbances was still recorded . of these , 32 ( 63% ) had migraine that was classified with aura in 11 of them . seven patients resulted to have been treated at some points with acetazolamide for migraine prophylaxis ( table  1 ) . before the introduction of acetazolamide , the mean frequency of migraine attacks was twice a week ( ranging from 1  attack / month to a daily disturbance ) . the duration of migraine attacks differed from one patient to another , and ranged from 30  min up to 1  week . in five of seven patients , two patients started experiencing somatosensory auras after having suffered for many years from migraine without aura . all patients had used some migraine symptomatic treatment , such as paracetamol , non - steroidal anti - inflammatory drugs , or triptans recording different degrees of response . one patient had been on migraine prophylaxis treatment before starting acetazolamide with paroxetine reporting only minimal benefit.table  1patients characteristics , drug treatment , and prophylaxis responsepatientsexagemigraine typenotch3 mutationdaily dose of acetazolamide ( mg)duration of treatmentresponseside effects1f56without auraexon 2 c.194 g  >  a ( p.cys65tyr)2505  monthsnonenone2f27without auraexon 6 c.1012 t  >  c ( p.cys338arg)1256  monthssignificant improvementnone3f41without auraexon 11 c.1819c  >  t ( p.arg607cys)2506  monthssignificant improvementnone4f48with somatosensory aura and aura without headache ( language disturbance)exon 19 c.3062a  >  g ( p.tyr1021cys)1256  years ( taken only on migraine attack)improvement in 1  hsubjective gastrointestinal disturbance5f68without auraexon 11 c.1819  >  t ( p.arg607cys)5006  monthsnonenone6f34with visual and somatosensory auraexon 11 c.1819  >  t ( p.arg607cys)2503  monthssignificant improvementnone7m56with somatosensory , visual and language disturbances auraexon 19 c.3016c  >  t ( p.arg1006cys)5001  yearimprovementmild increase of creatinine levels patients characteristics , drug treatment , and prophylaxis response the duration of prophylactic treatment with acetazolamide ranged from 3 to 12  months . drug treatment was empirically started at low dose ( 125  mg / day ) and gradually increased according to response or side effects . however , one patient deliberately took the drug only on the occasion of migraine episodes . in five out of seven patients , the treatment was effective with an obvious reduction in the frequency of migraine attacks . in three patients , the benefit could be appreciated within some days of starting of the treatment and produced a total and prolonged remission . in two patients , a reduction in the frequency and severity of attacks was recorded . in the patient taking acetazolamide only during migraine attack , the beneficial effect appeared in about 1  h ; her attacks were usually more prolonged . in two patients , when considering side effects , subjective gastrointestinal disturbances were reported by the patient , who took the drug only on the occasion of migraine attacks . the reported side effects indeed persisted after a first interruption of acetazolamide , and the drug was then started again because of worsening of migraine . in another patient , a mild increase in creatinine levels was recorded and this brought to decrease the daily dose of the drug from 500 to 250  mg . our preliminary data corroborate two previous single - case reports on the possible efficacy of the drug in this condition [ 8 , 9 ] . even if our data derive only from a retrospective database analysis and therefore no definitive conclusion can be derived , it has to be noted that the efficacy of the drug was quite striking with a net benefit reported by five out of seven patients early after drug starting . surprisingly , the rate of side effects reported by our cadasil patients appears somehow lower that that expected at least in common migraine . acetazolamide is a drug used for a variety of conditions such as congestive heart failure , some forms of epilepsy , glaucoma , idiopathic intracranial hypertension , but also rare diseases , such as acute mountain sickness . when considering central nervous system effects , acetazolamide penetrates the blood  brain barrier slowly , causes carbonic acidosis through carbonic anhydrase inhibition , and induces in normal subjects a considerable increase in cerebral blood flow by vasodilation . because of this effect , acetazolamide infusion is also used to evaluate the degree of alterations in cerebrovascular reactivity [ 13 , 14 ] . this effect may depend on a metabolic change induced by the enzyme blockage through a decrease in perivascular ph and increasing the concentration of nitric oxide or also by a direct effect on the wall of small brain arterioles and arteries , the real underlying mechanism still being unclear [ 16 , 17 ] . the acetazolamide - dependent cerebral vasoreactivity has been also assessed in cadasil . in this disease , the drug is able to produce an increase in cerebral perfusion as seen by transcranial doppler sonography , perfusion mri   or tc-99 m ecd brain perfusion spect . one study has investigated acetazolamide efficacy in sporadic migraine with and without aura , demonstrating a reduction in the frequency of attacks in both migraine types . the first one sees migraine deriving from cerebral oligemia [ 22 , 23 ] , and acetazolamide acting through vasodilatation . this last mechanism is the one thought to be responsible for the acetazolamide mechanism of action in familial ion channels disorders , such as familial hemiplegic migraine , hypokalemic periodic paralysis and episodic ataxia type 2 [ 2426 ] . one can hypothesize that one of the above - mentioned mechanisms or even both are present also in cadasil migraine . today , cadasil migraine is classified according to the international classification of headache disorders ( ichd-2 ) as headache attributed to cranial or cervical vascular disorder . however , it is known that , in this disease , migraine symptoms precede the onset of ischemic events by several years , and that the typical cadasil strokes are mostly of the subcortical type and associated with lacunar syndromes , whereas migraine - associated disturbances , such as dysphasia and visual aura are linked with cortical phenomena . one possible explanation for this seemingly discrepancy in cadasil could be to hypothesize the presence of an ultrastructural smooth muscle cells modification in the meningeal and cortical vessels . a second hypothesis sees the presence of a possible neuronal cell dysfunction , such as the above - reported changes in calcium channels or in glial sodium channels ( seen also in other hereditary diseases like familial hemiplegic migraine and mitochondrial disorders ) that have been already reported to be related to a higher level of brain hyperexcitability , suggesting a potential role in cadasil migraine . the complexity of the migraine mechanism in cadasil is also supported by the recently reported efficacy of intravenous sodium valproate in one patient with a combination of seizures and migraine . in conclusion , our data seem to hint at a significant effect of acetazolamide in cadasil migraine prophylaxis . our small series of cadasil patients expands the previous literature on the topic , but clearly it is numerically very limited and retrospective in nature , and therefore no final conclusion about the use of acetazolamide in cadasil migraine can be drawn at present . when considering the absence of data and the severity of the disturbance in cadasil patients , such a trial appears worthy to be started . in our opinion first , the systematic and controlled use of acetazolamide in cadasil could indirectly provide some information about the pathogenesis of the disease , particularly on the role of microvessels . second , a trial with acetazolamide could also provide some information about the possible effect of the drug on other disease disturbances . of note , one preliminary study has already shown that a 24-week administration of acetazolamide is able to improve cerebral hemodynamics in cadasil .
cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( cadasil ) is an inherited microangiopathy caused by notch3 mutations . 
 it is characterized by migraine , with or without aura , ischemic events , psychiatric and cognitive disturbances . 
 there is no approved treatment for migraine prophylaxis in cadasil , but acetazolamide has been anecdotally reported to be effective . 
 we retrospectively reviewed our database of patients with a genetic diagnosis of cadasil to identify how many of them were treated with acetazolamide for the prophylaxis of migraine . 
 the efficacy and the tolerability of this treatment were checked looking at the clinic reports . 
 acetazolamide was prescribed in seven patients ; the mean duration of treatment was 6  months , and the daily dose ranged from 125 to 500  mg . 
 three patients had a total and sustained remission , while in two patients a reduction in attacks and an improvement of the headache intensity were recorded . 
 in one of these , acetazolamide was deliberately taken only during the migraine attack and the beneficial effect started 1  h after administration . in two patients , the drug did not produce any beneficial effect . 
 mild side effects were recorded in two patients . 
 our preliminary experience expands previous reports and confirms the possible efficacy of acetazolamide in cadasil migraine . 
 based on these data , a randomized controlled trial seems worthy to be carried out to test the efficacy and safety of this drug .