Letters to the Editor 235 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.2.235 on 1 February 1996. Downloaded from

recently it has become clear that hypona- for the cerebral salt wasting syndrome, espe- her left arm. Six months later she com- traemia in the cerebral salt wasting syn- cially in more severe cases. plained of numbness and weakness of her drome is accompanied by hypovolaemia.' 2 WM MULLENERS left arm and leg, from which she recovered We a Departmnenit ofNeurology, report patient with cerebral salt WIM VERHAGEN slowly. No risk factors such as arterial wasting after aneurysmal subarachnoid RHMA BARTELS hypertension, diabetes, or migraine were haemorrhage who showed remarkable Departnieiit oflNeurosurgety, reported. Neurological examination showed changes in urine production during surgery. Caniisius Wilhelnmina Hospital, Nlzjmegeni, The Netherlands a slight left sided ataxia, hemiparesis, and A 46 year old woman was admitted with hypaesthesia. Neuropsychological testing severe headache and vomiting. Physical Correspondence to: Dr WIM Verhagen, Canisius showed reduced cognitive performance and examination was unremarkable. Brain CT Wilhelmina Ziekenhuis, Department of Neurology, a deficit in and PO Box 9015, 6500 GS Niimegen, The flexibility, learning memory, showed a subarachnoid haemorrhage with Netherlands. and abnormal visual constructional abilities blood in the suprasellar cisterns and the left which were compatible with a subcortical Sylvian fissure. Two days later she devel- 1 Nelson PB, Seif SM, Maroon JC, Robinson dementia. Brain MRI showed extensive oped mild hyponatraemia and polyuria; salt AG. Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate hyperintensive confluent lesions of the pari- and fluid loss were fully compensated by secretion of antidiuretic hormone (SIADH). etal and temporal white matter on both 0 9% NaCl infusion. On day 9 she was NATeurosurg 1981;55:938-41. sides, mainly in the periventricular and adja- found unconscious with respiratory failure 2 Wijdicks EFM, Vermeulen M, Ten Haaf JA, cent subcortical regions (fig 1). and bradycardia and CT disclosed a recur- Hijdra A, Bakker WH, Van Gijn J. Volume depletion and natriuresis in patients with a Family history showed that the mother of rent subarachnoid haemorrhage in the left ruptured intracranial aneurysm. Annii Neurol the patient died at the age of 52 with a his- Sylvian fissure. The patient regained con- 1985;18:21 1-6. tory of stroke and dementia. Two siblings sciousness and she gradually recovered from 3 Juul R, Edvinsson L, Ekman R, Frederiksen TA, Unsgard G, Gisvold SE. Atrial natri- had MRI changes similar to the index a mild aphasia and right facial weakness. uretic peptide-LI following subarachnoid patient, and one had had recurrent episodes However, from day 12 onwards she again haemorrhage in man. Acta Neurochir (Wien,) of aphasia, headache, and hemianopsia. Six developed a progressive polyuria of up to 1 990;106: 18-23. members of this family, three affected and 21 200 ml per day (on day 22) a 24 4 D6czi T, Bodosi M. The central neuro- and endocrine regulation of brain water and three healthy, have been genotyped with hour renal sodium loss of 2630 mmol. The electrolytes, and resorption of cerebrospinal eight chromosome 19 markers spanning the plasma sodium range was between 128 and fluid (CSF). In: Gjerris F, Borgesen SE, CADASIL interval. No recombinant was 142 mmol/l, and the colloid osmotic pres- Sorensen PS, eds. Outflow of cerebrospinial fluid. Alfred Be?zzoni S3yiposium"i 27. found with any of those markers. Maximum sure was between 18-7 and 24-0 mm Hg. Copenhagen: Munksgaard, 1989:282-90. lod scores were obtained with markers Serum ADH concentrations were normal. D19S226, D19S253, and D19S199, Treatment with fludrocortisone had no strongly suggesting that this family is linked effect on renal sodium loss. Despite the to the CADASIL locus. extreme polyuria plasma atrial natriuretic A 2 cm long segment of the sural nerve protein concentrations were within the nor- A patient with cerebral autosomal dom- was processed for light and electron mal range (up to 11-1 pmol/l, normal 3-23 inant arteriopathy with subcortical microscopy. Six fascicles were present. pmol/l); atrial natriuretic protein in CSF was infarcts and leucoencephalopathy Around 120 small and large vessels were not assessed. Daily transcranial Doppler (CADASIL) confirmed by sural nerve counted in the endoneurial and epineurial sonography was indicative of cerebral biopsy spaces. The largest epineurial arteries (size vasospasm and therefore angiography was up to 100 pm) appeared normal. Small postponed until day 22. An aneurysm of the "Cerebral autosomal dominant arteriopathy epineurial and endoneurial vessels were left middle cerebral artery was disclosed, with subcortical infarcts and leucoen- unchanged in paraffin sections. The arterio- which was successfully clipped on day 24. cephalopathy" (CADASIL) is a newly lar wall was not thickened on semi-thin sec- Whereas the diuresis 24 hours before and defined syndrome characterised, in the tions and no increase in number of nuclei after the neurosurgical procedure was absence of hypertension, by recurrent sub- was evident. The perineurium was not thick- 600-700 ml/hour, the mean intraoperative cortical ischaemic strokes and by peculiar ened and there was no increase of endo- (from incision to the last suture) production non-amyloid, non-arteriosclerotic angiopa- neurial connective tissue. The density of of urine was 150 ml/hour. The largest thy of cerebral vessels. On MRI circum- myelinated fibres was 6600/mm2 (normal reduction in diuresis was seen while the dura scribed subcortical ischaemic lesions and range for the sural nerve for this age was open. Soon after suturing the dura, diffuse areas of leucoaraiosis are seen both 6000-8000/mm2). Myelin degradation prod- http://jnnp.bmj.com/ urine production rose to preoperative values. in symptomatic and asymptomatic family ucts were not encountered. Two days after surgery diuresis decreased members.2 Recently, genetic linkage analysis Electron microscopy showed changes in a remarkably and was back to normal on the in two unrelated French families has few epineurial vessels, consisting of electron fourth day after operation. Repeated mea- assigned the disease locus to chromosome dense, extracellular granular deposits along surements of plasma sodium were also nor- 19q12 with the most likely location of the the outer aspects of the vessel walls (fig 2A). mal. The patient had fully recovered two disease gene between D19S221 and Most of these granules were on the ablumi- months after the operation. D19S222.1 nal surface of pericytes and less often on Our patient had a very pronounced uri- A few postmortem studies have been endothelial cells. Most granules measured nary sodium loss of up to 60 g per day. reported, showing predominant involvement 0-2 to 05 pm in diameter. However, some on September 27, 2021 by guest. Protected copyright. Opening of the dura resulted in a decrease of the cerebral white matter with diffuse measured up to 1-2 x 08,pm. Dense de- in diuresis of 75%. Both a reactive increase myelin loss, multiple small deep infarcts, posits were frequently located in thickened of CSF production and a decrease in the and occasional haemorrhages.2 As first basal laminae and were often pushing back intracranial pressure may have been impor- reported by Baudrimont et al, the small the cell membrane of an adjacent pericyte tant. Because an increase of atrial natriuretic subcortical and leptomeningeal arteries and (fig 2 B and C). Most dense deposits were protein in CSF (and maybe other humoral arterioles display fibrous thickening and an round or oval but some were flat or disc factors) results in a decrease in CSF produc- eosinophilic, periodic acid-Schiff (PAS) pos- shaped and oriented parallel to the cell sur- tion and an increase in natriuresis, an itive, granular material in the muscle layer. faces (fig 2A). The number of dense increase in CSF production after loss of Electron microscopy shows swollen myo- deposits ranged from none to five or six CSF through the open dura may have cytes in the media surrounded by collagen, around a single vessel. Some were found in induced a decrease of atrial natriuretic pro- elastin, and a compact electron dense mater- very small arterioles but most were in large tein, resulting in a decrease in natriuresis. ial.' capillaries or meta-arterioles (size 14-15 In patients with subarachnoid haemor- The arteriopathy of CADASIL is appar- pm) consisting of endothelial cells sur- rhage D6czi and Bodosi found a linear cor- ently not restricted to brain vessels as identi- rounded by pericytes but without the pres- relation between the intracranial pressure cal vascular lesions have been found in small ence of smooth muscle cells. In some and atrial natriuretic protein concentrations myocardial arteries' and sural nerve. vessels, the basal lamina the in surrounding CSF. So lowering the intracranial pres- We present a 55 year old woman with a endothelial cells was clearly redundant and sure might result in reduced concentrations history of recurrent pulmonary embolism tortuous (not shown). Many pinocytic vesi- of atrial natriuretic protein in CSF and lead from the age of 35. At the age of 40 she cles were found along and underneath the to an increase in CSF production and a experienced a feeling of heaviness in her left surface of cell membranes. Their density decrease in natriuresis. arm for about two days. Fifteen years later was not altered at the site of close apposition If either assumption is correct, continuous the patient described episodes of a burning to the cell membrane with the electron CSF drainage-for example, by an external sensation on her tongue and tingling as well dense granular deposits. lumbar drain-may be an effective treatment as weakness of the left side of her face and The presence of granular electron dense 236 Letters to the Editor J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.2.235 on 1 February 1996. Downloaded from

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* -.4w,....<,° .;r.S5.. . 8 . -.N§ -Sg Figure 1 T2 weighted MRI showing extensive hyperintensive lesions in the brainstemn, basal ganglia, and periventricular white matter of the index patient. material in the media of leptomeningeal and small cerebral penetrating arteries is consid- ered to be a characteristic ultrastructural feature of CADASIL.2 The pathophysiolog- ical relevance of these lesions is unknown and their specificity has still to be estab- lished. Deposition of an identical material has also been reported in small vessels of a sural nerve obtained from a patient with sus- F:-;:A i:V;F pected CADASIL.4 Here we present a patient with very similar ultrastuctural find- ings in a sural nerve biopsy and who was ... diagnosed as CADASIL based on clinical data, neuroimaging features, and genetic linkage analysis. Ultrastructural changes in the nerve biopsy of this patient, apart from electron dense deposits along abluminal sur- faces of endothelial cells and pericytes, were characterised by redundant basal membrane

type material, possibly pointing to some http://jnnp.bmj.com/ metabolic disturbance in extracellular matrix production by endothelial cells, pericytes, and possibly myocytes in larger vessels. The typical fine structural lesions encountered in epineurial or transperineurial capillaries,' meta-arterioles, or small arterioles of sural Figure 2 (A) Low power electroni micrograph of a small epineurial arteriole of the sural 7nerve. nerve hardly have any light microscopical Several electroni dense, rounid, or disc shaped precipitates (arrows) can be seen in the basal laminla equivalent. In addition, large epineurial ves- surrounding pericytes (P). E = Enidothelial cells; scale bar = 1 pmii. (B) Higher miiagniification of the area in fig 2A showinlg one electroni dense granular deposit (gd) emiibedded in basal sels seemed to be normal. Thus diagnostic mnarked on September 27, 2021 by guest. Protected copyright. lamina material. pv = Pinocytic vesicles; cf = collagen fibrils; scale bar = 0 2 pmii. (C) Another confirmation of CADASIL by sural nerve example of dense granular deposit (gd) found in a smtiall epineurial vessel, emiibedded in the basal biopsy clearly requires electron microscopy. lamina (bl) of a pericyte (P); scale bar = 02 pum. The same applies to other tissues, as recently shown by Ruchoux et al.' Perform- ing skin and muscle biopsies in several members of a family with known CADASIL, and sural nerve biopsies, in establishing the with subcortical infarcts and leukoen- these authors found non-specific light diagnosis of CADASIL. cephalopathy maps to chromosome 19q12. tissues. Nature Genietics 1993;3:256-9. microscopical changes in biopsied 2 Gray F, Robert F, Labrecque R, et al. Auto- Electron microscopy showed thickened vas- We thank Dr E Tl ournier-Lasserve and Dr K somal dominant arteriopathic leuko- cular basal lamina of capillaries and arteri- Vahedi for performing linkage analysis. encephalopathy and Alzheimer's disease. oles with diameters from 10 to 50 pm and LECHNER-SCOTT oNeropathol Appl Neirobiol 1 994;20:22-30. J 3 Baudrimont M, Dubas F, Joutel A, Tournier- patches of granular and electron dense S ENGELTER Lasserve E, Bousser MG. Autosomal domi- A J STECK material close to the cell membrane of vas- nant leukoencephalopathy and subcortical cular smooth muscle cells. These and our Departmewt of Neiurology ischemic stroke. A clinicopathological study. S DELLAS Stroke 1 993;24: 122-5. the Departtoncnit of Radiology own findings indicate that vasculopathy 4 Schroder JM, Sellhaus B, Jorg J. Identification of CADASIL is more widespread than ini- M TOLNAY in A PROBST of the characteristic vascular changes a nerve of a case with tially reported, despite the fact that, until Inisti'tute of Pathology, sural biopsy cerebral vessel pathology has been cerebral autosomal arteriopathy with sub- now, only Kanitonisspital Basel, Basel, Szvitzerlanid cortical infarcts and leukoencephalopathy shown to be of relevance by causing strokes (CADASIL). Acta Neuropathol 1995;89: evi- Correspondence to: Professor A J Steck, Depart- and dementia. Present morphological Peters- 116 21. ment of Neurology, Kantonsspital Basel, 5 Chabriat H, Bousse, dence points to a diffuse microangiopathy graben 4 CH 4031 Basel, Switzerland. Ruchoux MM, M-G, are Baudrimont M, Tournier-Lasserve E. throughout the body. More studies Presence of ultrastructural arterial lesions in needed to compare the respective values, 1 Tournier-Lasserve E, Joutel A, Melki J, et al. muscle and skin vessels of patients with especially the sensitivity, of skin, muscle, Cerebral autosomal dominant arteriopathy CADASIL. Stroke 1994j25:2291-2.