Hereditary endotheliopathy with retinopathy, nephropathy, and stroke(HERNS) J. Jen, A. H. Cohen, Q. Yue, et al. Neurology 1997;49;1322-1330 DOI 10.1212/WNL.49.5.1322 This information is current as of November 1, 1997 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/49/5/1322.full.html Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. aphasia during left-hemisphere anesthesia. Neurology 1995; 45:65-67. 22. Buchtel HA, Henry TR, Ahou-Khalil B. Memory for neurological deficits during the intracarotid amytal procedure: a hemispheric difference. J Clin Exp Neuropsychol 1992;14:96-97. 23. Kaplan RF, Meadows ME, Cohen RA, Bromfield EB, Ehrenberg BL. Awareness of deficit after the sodium amobarbital (Wada) test [abstract]. J Clin Exp Neuropsychol 1993;15:383. 24. Durkin Mw, Meador KJ, Nichols ME, Lee GP, Loring DW. Anosognosia and the intracarotid amobarbital procedure (Wada test). Neurology 1994;44:978-979. 25. Carpenter K, Berti A, Oxbury S, Molyneux AJ, Bisiach E, Oxbury JM. Awareness of and memory for arm weakness during intracarotid sodium amytal testing. Brain 1995;118: 243-251. 26. Myers JL, DiCecco JV,White JB, Borden VM.Repeated measurements on dichotomous variables: Q and F tests. Psycho1 Bull 1982;92:517-525. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) J. Jen, MD, PhD; A.H. Cohen, MD; Q. Yue, MD; J.T. Stout, MD, PhD; H.V. Vinters, MD; S. Nelson, MD; and R.W. Baloh, MD Article abstract-We describe a Chinese American family with a hereditary syndrome consisting of retinopathy, nephropathy, and stroke, affecting 11 members spanning three generations. Ophthalmologic evaluations revealed macular edema with capillary dropout and perifoveal microangiopathic telangiectases. Several members had renal abnormalities with proteinuria and hematuria. Initial manifestations were visual impairment and renal dysfunction; neurologic deficits occurred in the third or fourth decade of life. Symptoms included migraine-like headache, psychiatric disturbance, dysarthria, hemiparesis, and apraxia. Neuroimaging consistently demonstrated contrast-enhancing subcortical lesions with surrounding edema. Ultrastructural studies showed distinctive multilaminated vascular basement membranes in the brain and in other tissues, including the kidney, stomach, appendix, omentum, and skin. Genetic analysis ruled out linkage to the CADASIL locus on chromosome 19. Distinct from CADASIL, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is an autosomal dominant multi-infarct syndrome with systemic involvement. NEUROLOGY 1997;49:1322-1330 Multi-infarct syndrome is characterized clinically by progressive neuropsychiatric deterioration and radiographically by multiple subcortical white matter lesions. It is generally sporadic, associated with aging and hypertension; occasionally, it can be inherited. The mechanism underlying multifocal white matter disease is not well understood. Elucidating the pathophysiology in familial multi-infarct syndromes may shed light on mechanisms of white matter injury in general. In 1977, Sourander and Wilinder’ reported a family with hereditary progressive leukoencephalopathy in middle-aged adults without hypertension. That family is probably the first reported case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an autosomal dominant syndrome mapped to chromosome 1g2and recently found to result from mutations in the human Notch3 gene.3 How these mutations lead to the vasculopathy is unknown. In 1988, Grand et al.4 reported a large family with clinical features similar to CADASIL; in addition, family members developed visual loss due to characteristic retinal capillary abnormalities. Gutmann et al.5 later described another family with a similar syndrome of progressive visual loss and leukoencephalopathy without any renal or other organ involvement. We report on a Chinese family, with 11 affected members spanning three generations, who manifested a hereditary vasculopathy similar to cerebroretinal vascu10pathy,4.~with subcortical leukoencephalopathy and retinopathy, as well as renal dysfunction. Genetic analysis ruled out linkage to the CADASIL locus on 19p. Ultrastructural studies identified characteristic alterations of vascular basement membranes not previously described. From the Departments of Neurology (Drs. Jen, Yue, and Baloh), Pathology and Laboratory Medicine (Drs. Cohen and Vinters), Medicine (Dr. Cohen), Pediatrics (Dr. Nelson), and Surgery (Dr. Baloh), UCLA School of Medicine; Department of Pathology (Dr. Cohen), Cedars-Sinai Medical Center; and Departments of Ophthalmology and Cell and Neurobiology (Dr. Stout), USC School of Medicine, Los Angeles, CA. Supported by NIH grants AG9063, DC02952, DC00008-20 and PHS P30AG10123, POlAG12435. Received April 7, 1997. Accepted in final form June 17, 1997. Address correspondence and reprint requests to Dr. R.W.Baloh, Department of Neurology, UCLA School of Medicine, Box 951769, 710 Westwood Plaza, Los Angeles, CA 90095-1769. 1322 Copyright 0 1997 by the American Academy of Neurology I I II Figure 1. Pedigree shows an autosoma1 dominant pattern of inheritance spanning three generations. Closed figures indicate subjects were affected; asterisks indicate subjects were examined. Case reports. Clinical history was obtained from patient interviews. Six members from this kindred were examined. Medical records of these members as well as those deceased (111-3, 111-6, 111-14, 111-17) were reviewed. The pedigree is shown in figure 1. Table 1 summarizes the clinical features of affected members. Patient 1 (pedigree 111-3). This ambidextrous man was 28 when he first noted blind spots in his visual field. He had retinal vasculopathy of unclear etiology and underwent laser treatment. At age 32, while working as an artist painting portraits for royalty in Saudi Arabia, the patient noted the sudden onset of right-hand weakness, which rapidly progressed to involve his right leg. Head CT showed a 2-cm ring-enhancing deep white matter lesion in the left frontoparietal region with surrounding edema. Corticosteroids provided some clinical improvement. He underwent subtotal excision of the left frontal lesion, a presumed malignancy. After a follow-up scan showed progression of the lesion, he underwent a second biopsy. Postoperatively, the patient became discouraged and depressed, then committed suicide. Detailed information regarding his renal function was not available except that he had 2+ proteinuria, with urea nitrogen of 19 mg/dL and creatinine of 1.4 mg/dL. An autopsy was not performed. Patient 2 (pedigree 111-11). A 45-year-old right-handed man with a long-standing history of anxiety presented at age 42 complaining of insidious onset of stuttering speech. At age 32, he had noted blind spots in his visual field, but had no focal neurologic deficits. Ophthalmologic evaluation at that time revealed focal areas of macular edema associated with capillary telangiectasis (figure 2). Focal laser photocoagulation was applied to these areas, and the edema largely resolved. Over the course of the next 5 years, additional areas of macular edema evolved and spontaneously resolved without further photocoagulation. Brain MRI showed no focal lesion (figure 3A). At the time of initial presentation with neurologic complaints, the then 42-year-old patient exhibited only verbal stuttering, diffuse hyperreflexia, and severe anxiety, with an otherwise normal neurologic examination. Serum and CSF examinations were all normal. Brain MRI demonstrated multiple high T2 signal intensity (figure 3B) and gadolinium-enhancinglesions in the paraventricular white matter and corpus collosum (figure 3C). A brief course of corticosteroid treatment was of no benefit. The patient subsequently developed progressive limb paresis, apraxia, and dementia. Follow-up brain MRI a year later showed progression of the subcortical lesions that had become confluent (figure 3D). Serum creatinine level was 1.7 mg/dL, with trace albuminuria and hematuria (5 RBC/HPF). The patient was bedridden and demented by age forty-four. Patient 3 (pedigree 111-2). A 36-year-old, right-handed woman first noted blind spots in her visual field with un- Table 1 Clinical features of affected family members Sex Age a t onset of neurologic deficits (y) Age at death (y) 1-1 F 50 60 11-2 F 39 44 11-5 F 43 52 111-2 F 31 35 + + + + 111-3 M 32 32 Unknown 111-6 M 36 I 111-9 M - + 111-10 F 40 Unknown - Family member Migraine headache 111-11 M 42 111-14 F 39 44 Unknown 111-17 M 40s 51 + Retinopathy + + + + + + + + + + + Stroke-like episodes and dementia + + + + + + Psychiatric disturbance Renal insufficiency and proteinuria Subcortical lesions on Unknown Unknown CT/MRI Unknown + - Unknown Unknown - + + + - + - - - - + + + + + + + + Unknown f + + 4- + Unknown F = female; M = male; + = symptom was experienced by patient; - = symptom was not experienced by patient. November 1997 NEUROLOGY 49 1323 Figure 2. Mid-venous phase fluorescein angiogram from patient III-11 demonstrating areas of macular capillary dropout as well as dilated tortuous telangiectatic vessels and capillary shunts. impaired visual acuity at age thirty-one. Having cared for her mother and her two brothers when they fell ill, the patient anticipated neurologic deterioration to follow the onset of scotomata. With the development of blind spots, the patient experienced onset of frequent right-sided headaches that were occasionally preceded by visual aura. Though neurologically asymptomatic at the time, she underwent a brain MRI, which revealed no focal lesions. At age 34, still neurologically normal, she had a repeat brain MRI which showed multiple small high-intensity signals bilaterally on T2-weighted images (figure 4A). At age 36, she noticed slight clumsiness in her left hand while typing. Within a week, the weakness had progressed to involve her left leg. A brain MRI showed two subcortical contrast-enhancing lesions with surrounding edema in the right frontoparietal region (figure 4B). A month after the onset of left hemiparesis, she developed blurred vision and a persistent pressure-like headache that was worse while lying down, mostly involving her right eye and the right side of her head. One night she had projectile vomiting without nausea. She remained awake, alert, ambulatory, with reactive pupils but slightly blurred disk margins. Brain MRI showed increased size of the lesions with pronounced vasogenic edema and impending herniation (figure 4C). She was admitted to the intensive care unit and treated with high doses of corticosteroids. Within a few days, much of the edema had resolved (figure 4D). Corticosteroids were slowly tapered, and she remained neurologically unchanged. At the time of the diagnosis of retinal vasculopathy at age 31, she had renal insufficiency manifested by elevated serum creatinine to 2.5 mg/dL, proteinuria (300 mg/dL), and hematuria (15 to 20 RBCMPF). 1324 NEUROLOGY 49 November 1997 Methods. Ophthalmologic examination. Fluorescein angiography was performed in five patients (111-2, 111-3, 111-9, 111-10, 111-11)using standard procedures involving the injection of 5 mL of aqueous fluorescein dye in the antecubital vein followed by serial photographs over 20 minutes. Neuroimaging studies. Brain CTs from three deceased patients (111-3, 111-6, 111-14) were reviewed. Brain MRI (Tl- and T2-weighted axial sections with contrast) was carried out in six patients (111-2, 111-4, 111-9, 111-10, 111-11, 111-19). Histologic studies. Formalin-fixed, paraffin-embedded sections from two (111-3, 111-14) patients' brain biopsies were obtained from Taiwan and studied by light microscopy. The specimens were reprocessed for electron microscopy.6 Kidney biopsy specimen was obtained from patient 111-2 to evaluate the nature of renal dysfunction. The renal specimen was processed in the standard manner for light microscopy, electron microscopy, and immunofluorescence.7 The patient later underwent appendectomy for abdominal discomfort; her intestinal tissue was paraffinembedded for light microscopy and later reprocessed for electron microscopy, as above. A skin biopsy specimen for light and electron microscopy was obtained from the same patient to investigate possible systemic involvement. Gastric tissue from patient 111-9became available for light and electron microscopic examination when he had elective endoscopy with biopsy. Genetic studies. For genetic linkage analysis, after obtaining informed consent of family members, we isolated DNA from peripheral bloods and typed a series of microsatellite markers on chromosome 19p9 with the following loci: D19S413-5cM-D19S221-6cM-D19S226-lcM-D19S841/ D19S253.1°We used the MLINK option in FASTLINK" for two-point linkage analysis, assuming autosomal dominant inheritance of a rare gene (population frequency 0.0001). Results. Clinical data. This large kindred of Chinese descent has 11affected individuals spanning three generations (see figure l and table l).Progressive visual loss typically began in the third and fourth decades of life in affected individuals, followed by focal neurologic deficits within 4 to 10 years. Many affected individuals had longstanding psychiatric symptoms (depression, anxiety, paranoia) with onset in the late second decade of life. Migraine was common (1-1,11-2, 111-2, 111-6, 111-3). Signs of multifocal cortical and subcortical dysfunction such as dysarthria, hemiparesis, apraxia, ataxia, and dementia were also common. In addition, several members had renal dysfunction (111-2,111-9,111-11),with azotemia, proteinuria, or hematuria; none required dialysis. Fluorescein angiography. Fluorescein angiograms showed juxtafovealar capillary obliteration with tortuous telangiectatic microaneurysms in all five affected members who were examined (see figure 2). Neuroimaging. Three patients (111-2,111-9,111-10)with initial retinal involvement had multifocal T2 high signal intensity lesions in the deep white matter on MRI before neurologic symptoms and signs developed. With the onset of focal neurologic deficits, the patients had contrastenhancing lesions with surrounding vasogenic edema, most commonly in the deep frontoparietal regions. Histopathology. Brain biopsy from patient 111-3 disclosed several abnormalities. Many fragments showed fea- Figure 3. Brain MRIs of patient III-11. (A) Visual complaints at age 32 but prior to the development of focal neurologic abnormalities, no focal lesion on T2-weighted images. (B) Dysarthria, hyperreflexia, and severe anxiety at age 42, multiple hyperintense T2-weighted lesions in the paraventricular white matter and the corpus collosum. (C) The lesions in panel B enhance after gadolinium injection on TI-weighted images. (D) Within a year, multifocal subcortical lesions coalesce to form large confluent areas of abnormal T2-weighted signal intensity. tures of a subacute cerebral infarct, with extensive nuclear fragmentation and spongy change, often centered on small blood vessels occluded by fibrin thrombi. Neurons were surrounded by significant edema. No inflammation was observed in the leptomeninges. No senile plaques, neurofibrillary tangles, or cerebral amyloid angiopathy were iden- tified. There was no evidence of a neoplasm or a vasculitis. There was intense subpial and subcortical white matter astrocytic gliosis. Material from available tissue blocks reprocessed for electron microscopy was suboptimal for detailed evaluation; however, multilayered appearance to the capillary basement membrane was noted (figure 5A). November 1997 NEUROLOGY 49 1326 Figure 4. Brain MRIs of patient 111-2. (A)Neurologically asymptomatic except for migraine-like headache with onset of retinopathy at age 31, multiple small subcortical hyperintense lesions on T2-weighted images. (B) Slight clumsiness in her left hand and left leg at age 36, contrast-enhancing lesions with surrounding edema in the right frontoparietal subcortical region on T1-weighted images. (C)Persistent headache with a n episode of projectile vomiting but no other neurologic changes, increased size of the lesions with marked edema and mass effect on proton-weighted images. (0)After 3 days of intravenous Decadron, decreased edema on proton-weighted images. Renal specimen by light microscopy displayed irregularly thickened capillary walls and slightly widened mesangial regions. By electron microscopy, most glomerular capillary 1326 NEUROLOGY 49 November 1997 walls were thickened, oRen with peripheral migration and interposition of mesangial cells. The original (subepithelial) basement membranes were normal; however, subendothelial Figure 5. Electron microscopic appearance of vessels. (A)Brain, patient 111-3.Reprocessed specimen with several layers of basement membrane (arrow) in cerebral capillary (X 11,000, before 32% reduction). (B) Normal glomerular capillary wall from age-matched control to patient 111-2.Note uniform appearance and thickness of basement membrane (arrow) (ve = visceral epithelial cell, e = endothelial cell) (XlO,OOO, before 32% reduction). (C) Glomerular capillary wall, patient III-2. The original basement membrane (arrow) beneath visceral epithelial cell (ve), while somewhat wrinkled, approaches a normal appearance. The basement membrane (arrowheads) beneath endothelial cell (e) is multilayered. A mesangial cell (m) separates the two basement membranes (X 12,800, before 30% reduction). (D)Renal peritubular capillary (patient 111-2)with multilayered basement membrane (arrow) beneath endothelial cell (X 10,000, before 32% reduction). (E) Cutaneous vessel (patient 111-2)with similar multilayered basement membrane changes (arrow) (X 11,400, before 32% reduction). (F) Gastric mucosa (patient III-9)with multilayered capillary basement membrane (arrow) (X9,900,before 30% reduction). basement membranes were multilayered with alternating medium dense and lucent zones (figure 5, B and C). Endothelial cell cytoplasm was normal or slightly swollen. Similar changes were noted in glomerular capillary walls without mesangial interposition. Basement membranes of peritubular capillaries and beneath arterial and arteriolar endothelial cells were also multilayered with an appearance identical to that described for glomerular capillaries (figure 5D).Tubular basement membranes had a normal appearance or were irregularly thickened in atrophic structures. Ultrastructural examination of appendix, omentum, and skin (figure 5E) of patient 111-2 and gastric tissue from 111-9 (figure 5F) disclosed multilayered basement membranes, similar to the above, beneath endothelial cells of capillaries, arterioles, and venules. There was no evidence of either abnormal mitochondria or accumulation of mitochondria in any tissue examined by electron microscopy. Genetic studies. Linkage analysis was performed to determine whether the vasculopathy in this kindred was linked to the CADASIL locus. The painvise linkage data, with the assumption that the disease is caused by a single defective gene with dominant inheritance, are given in table 2. At a recombination fraction of 0.0 all of the markers had a lod score of -3 or less. For marker D19S841, reported to have the highest combined lod score in families with CADASIL,12the lod score in our family was negative at a recombination fraction of 0.05. This linkage data makes it extremely unlikely that the Notch3 mutation on 19p causing CADASIL is involved in the pathogenesis of hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) in this kindred. Discussion. We report a syndrome of retinopathy, nephropathy, and recurrent strokes with a hereditary November 1997 NEUROLOGY 49 1327 Table 2 Results of pairwise linkage analyses of chromosome 19 lod score at 8 = Marker 0 0.01 0.05 0.1 0.2 0.3 0.4 D19S413 -4.53622 -0.854223 -0.223966 -0.01026 D19S221 -2.9999 0.182049 0.83045 1.023206 0.113 139 0.111679 0.065115 1.013965 0.793097 0.449216 D19S226 -3.77144 0.181826 0.830424 1.023194 1.013962 0.793096 0.449216 D19S841 -5.74242 - 1.558315 D19S253 -5.175697 - 1.604074 -0.715162 -0.339933 -0.045479 0.0248 0.013328 -0.739067 -0.347303 -0.040075 0.02997 0.014812 terized mainly by normal endothelial cells and basal pattern most consistent with autosomal dominant inlamina but concentrically thickened media of cerebral heritance. The underlying mechanism appears to be microvessels, which on ultrastructural examination a generalized vasculopathy with disruption of the shows an electron dense granular material interintegrity of capillaries and arterioles. Fluorescein angiograms clearly demonstrate retinal vasculopathic spersed among the smooth muscle layer extending into changes. That the intracerebral lesions showed the adventitia.14J5HERNS is characterized by a micontrast enhancement on imaging studies indicates croangiopathy with markedly thickened, multilayered breakdown of the blood-brain barrier. The surrounding subendothelial basement membranes. Further eviedema in a vasogenic pattern also suggests increased dence for the distinction between HERNS and CADASIL is the absence of linkage to the CADASIL locus on capillary permeability. Furthermore, findings from renal, skin, and gastric biopsy specimens demonstrate chromosome 19. Locus heterogeneity in hereditary systemic basement membrane abnormalities. Since multi-inf'arct dementia has been reported by others.l6 basement membrane is synthesized by the endothelial Progressive neuropsychiatric deterioration is comcells, the basement membrane abnormalities may remon t o Binswanger subcortical leukoencephalopathy flect primary endothelial injury. (BSL), CADASIL, hereditary cerebroretinal vascuThe radiologic findings of contrast-enhancing, lopathy, and HERNS (table 3). These symptoms and space-occupying lesions in the frontoparietal region signs are most likely manifestations of diffuse CNS and the clinical profile of cerebral and retinal indamage brought about by multifactorial mechavolvement in patients of this kindred are similar to n i s m ~ Similarly, .~~ migraine-like headache, another common feature, may reflect vasculopathy without those reported in hereditary cerebroretinal vasculopathy, which is of autosomal dominant i n h e r i t a n ~ e . ~ . ~regard to specific pathogenesis. However, renal insufficiency seen in this kindred is not The clinical significance and the pathologic basis of white matter signal changes remain poorly undera feature in the latter entity. It is unclear whether HERNS is the same as cerebroretinal vasc~lopathy,4~~stood. Breakdown of the blood-brain barrier resultwhere only limited light microscopic findings are ing in increased vascular permeability appears to be available and no systemic involvement has been docuthe common final pathway in all the multi-infarct mented. Electron microscopic examination of the syndromes. Endothelial injury brings about major biopsy specimens from affected members of other biochemical changes: increased oxygen free radical pedigrees may help clarify whether the vasculopathic formation; increased production of endothelial, features in these families are similar. smooth-muscle cell, and astrocytic mitogens as well Although pedigree in this kindred raises the possias chemotactic factors for neutrophils and fibrobility of maternal transmission, the pathologic findings blasts; release of vasoactive compounds such as hisin HERNS are not consistent with a mitochondrial tamine and endothelin; decreased prostacyclin; and disorder. Multifocal cortical and subcortical lesions in decreased plasminogen activator a ~ t i v i t y . ' ~These J~ patients with mitochondrial myopathy, encephalopabiochemical changes may lead to endothelial proliferthy, lactic acidosis, and stroke-like episodes ( M E W ) ation, perivascular inflammation, astrocyte and are thought to result from mitochondrial angiopathy, smooth muscle cell proliferation, thrombus formacharacterized by accumulations of abnormal mitochontion, and vasoconstriction. Increased filter permedria in vascular smooth muscle and endothelial ~el1s.l~ ability and focal brain edema contribute t o cerebral In this kindred, we observed no abnormal mitochontissue injury. dria or accumulation of these organelles in tissues Endothelial injury is common to many disorders, processed for ultrastructural studies. Furthermore, including hypertension, thrombotic microangiopamultilaminated basement membrane, a prominent thies, diabetes mellitus, immunologically mediated finding in HERNS, has not been reported in mitochoninjury, metabolic damage, and, probably, Alzheimer's drial angiopathy. The microangiopathy in H E W S is disease.20s21In the more common disorders with unlikely to result from mitochondrial abnormality. morphologic abnormalities of capillary basement This kindred has a vasculopathic process distinct membranes such as diabetes mellitus, glomerular from CADASIL. Pathologically, CADASIL is characcapillaries typically show uniform thickening of 1328 NEUROLOGY 49 November 1997 Table 3 Comparison of leukoencephalopathic syndromes Syndrome Heredity Binswanger subcortical leukoencephalopathy (BSL) Sporadic Mitochondrial myopathy, encephalopathy , lactic acidosis, stroke-like episodes (MELAS) Clinical features Radiographic features Vasculopathic features Non-contrast-enhancing white matter high T2 signal 1esion s Thickened, hyalinized arterioles Maternal Seizures, alternating transmission hemiparesis Multifocal gray and white matter high T2 signal lesions Mitochondrial angiopathy with accumulation of abnormal mitochondria in swollen cerebral capillary endothelial cells and arteriolar smooth muscle cells CADMIL Autosomal dominant Strokes, migraine, mood disorders, dementia Non-contrast-enhancing white matter high T2 signal lesions Systemic non-atheromatous, non-amyloid arteriopathy with destruction of the vascular smooth muscle cells and the formation of granular, electron-dense, eosinophilic material Hereditary cerebroretinal vasculopathy Autosomal dominant Strokes, retinopathy, dementia Contrast-enhancing white matter lesions with vasogenic edema Fibrinoid necrosis without inflammation? *Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) Autosomal dominant Strokes, retinopathy, nephropathy, migraine, mood disorders, dementia Contrast-enhancing white matter lesions with vasogenic edema Systemic vasculopathic changes with multilaminated basement membrane Strokes, mood disorders, dementia * This report. t Light microscopy only. basement membrane.20 Galloway-Mowat syndrome, a rare inherited disorder of microcephaly, nephrotic syndrome, and hiatal hernia,22is characterized by thickened but structurally disorganized glomerular basement membrane with normal endothelial cells and basement membranes in non-renal None of these disorders exhibit the characteristic multilayering of basement membrane seen in the kindred we describe. It should be noted, however, that multilayering of peritubular capillary basement membranes is common in chronic renal transplant rejection and has been considered a manifestation of recurrent endothelial cell injury in this setting. I t is unclear why a generalized vasculopathy should preferentially affect the brain, the retina, and the kidney. One explanation may be that these organs rely heavily on an intact endothelial barrier to maintain proper function and are particularly “eloquent” when injured. Furthermore, the basis for the regional vulnerability in the brain is intriguing in that the intracranial mass lesions tended to involve the frontoparietal region in both HERNS and cerebroretinal vasculopathy. It is also puzzling that, although focal edema was noted in brain tissues from the various syndromes, white matter lesions on neuroradiologic studies of BSL and CADASIL do not show contrast enhancement, whereas those in hereditary cerebroretinal vasculopathy and in HERNS do. Differences in the types of vessels affected and chronicity may account for the discrepancy we observe in these various multi-infarct syndromes. One possible explanation is that the vasculopathy in BSL and CADASIL involves mainly arterioles, whereas the smaller vessels are affected in hereditary cerebroretinal vasculopathy and HERNS. The progression of disease is much more rapid in the latter conditions, making it more difficult for the brain to compensate for markedly increased edema. There is no effective treatment to offer patients with HERNS. Aspirin, with its antiplatelet actions, has not shown any benefit in several patients in this family. Resection of the “pseudotumor” has not helped those who underwent this procedure, nor has laser treatment been shown to control retinal vasculopathy. Other than supportive care (e.g., physical therapy, corticosteroid to minimize cerebral edema, and antihypertensive medication for renal diseaseinduced hypertension), treatment would ideally be aimed at maintaining the integrity of the capillaries as well as prevention of the progression of white matter damage. Grand et al.4 noted the histologic similarities between hereditary cerebroretinal vasculopathy and delayed radiation-induced cerebral necrosis. Delayed cerebral radiation necrosis appears to result from damage of the endothelial cells of small vessels.24 The observation of similarities between hereditary cerebroretinal vasculopathy and delayed radiation-induced cerebral necrosis may have important therapeutic implications since anticoagulation may arrest and reverse endothelial injury and has been shown to produce clinical imNovember 1997 NEUROLOGY 49 1329 provement in some patients with the latter conditi~n.~~ In addition to CADASIL and HERNS,we anticipate recognition of other forms of hereditary vasculopathy with systemic involvement. In patients with familial multi-infarct syndrome, skin biopsy with careful ultrastructural examination may provide much needed pathologic details. References 1. Sourander P, WBlinder J. Hereditary multi-infarct dementia. Acta Neuropathol (Berl) 1977;39:247-254. 2. Tournier-Lasserve E, Iba-Zizen M-T, Romero N, Bousser M-G. 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