Folia Psychiatrica et Neurologica Japonica, Vol. 29, No. 3, 1975 Involvement of Central Nervous System in Pseudoxanthoma Elasticum Katsuya Goto, M.D. Division of Neurology, Kyushu Kosei-Nenkin Hospital, Kitakyushu INTRODUCTION CASE REPORT Pseudoxanthoma elasticum is a rare disease which has a tendency to develop multiple papule resembling xanthoma in the neck, axillae, cubital and knee joints and abdominal wall. Accompanying to the skin lesion, “angioid” streaks, dark blue to brown in color, are often found in the optic fundi. And this combination is sometimes called Gronblad-Strandberg syndrome. In recent years, it has come to attract the attention of the internists because of rather frequent occurrence of massive gastric hemorrhage, hypertension and cardiovascular disorders in the course of this disease and abbreviation “PXE’ is often used for the designation of the entire ~ y n d r o m el7. ~ And it has long been known that central nervous complications occur sporadically in this disease. But detailed reports on such cases are very rare, and to my knowledge there is no literature in which neurological complications are reviewed. The present paper is a report on a case of pseudoxanthoma elasticum with epilepsy, progressive mental deterioration and multiple focal neurological abnormalities, and a review of the literature of pseudoxanthoma elasticum with special reference to the central nervous abnormalities. A 24-year-old female was first referred for neurological evaluation in 197 1 because of frequent epileptic attacks. She had been in good health until the age of 12, when she gradually developed multiple papules on the neck and abdominal wall. About this time, it was pointed out by a physician that her radial pulsation was absent bilaterally. The skin eruption did not show any tendency of healing but became more prominent. At the age of 17, she often complained of weakness of memory and difficulty in concentrating her attention on a subject. And her family noticed that she had become highly irritable and shorttempered. In subsequent years, there was a marked decline in her scholastic attainments. At the age of 18, clonic convulsive seizure occurred in her left hand and then spread to the whole of her body. After about half an hour, she regained her sense, but dreamy state continued €or a week or so. Thereafter, the administration of the anticonvulsant drugs was started. But convulsive seizures occurred once or twice a month, most of which started from left hand and followed by Jacksonian march, but sometimes generalized convulsion occurred from the beginning. She could not engage in any occupation other than baby-sitting after graduating from high school. Her mother’s pregnancy, labor and delivery were uncomplicated. Growth and de- Received for publication Jan. 13, 1975. K. Goto is now at the Department of Radiology, Akita University School of Medicine, Akita. 264 K. Goto velopment during her childhood were normal. There was no history of previous convulsion of any type. No consanguinity could be traced. There was no family history of similar skin disease, epilepsy and other neurological and psychic disorders. She was admitted to the Division of Neurology in Kyushu Kosei-Nenkin Hospital in August 1971. The physical examination on admission revealed: a well nourished, but rather smail female in somewhat depressive mood. The pulsation of bilateral radial, dorsalis pedis and posterior tibia1 arteries were absent. But the brachial and popliteal pulsations were well palpable. The murmurs on both carotid and femoral arteries were absent bilaterally. Blood pressure on her right arm was 116/70. Heart sounds were normal and there were no abnormal murmur. The skin of her neck was loose. There were numerous acne-like papules on the neck, and multiple, small perforations of the skin of irregular shape were scattered among them. The papules fused together in the Ieft temporal area and formed keroid-like atrophic plaque (Figs. 1-2). The ophthalmoscopic examination revealed no papilledema nor optic atrophy. But abnormal striae, dark blue in color, radiating from the disc and numerous fine dots, yellowish brown in color, around the disc were observed in both fundi (Fig. 3). But her visual acuity was normal. She was alert mentally and well orientated to time, place and person. Aphasia, apraxia, agnosia and other disturbances in higher cortical functions were not observed practically. The neurological examination revealed no visual field defect, no abnormality in the ocular movement and no nystagmus. The sensation of the face was normal, and there was no weakness of masseter, temporal and facial muscles. Difficulty in hearing, tinnitus and vertigo were not noticed. The movement of soft palate was normal, and there was no difficulty of articulation and swallowing. Mild weakness and increase in DTR were noticed in her right upper and lower extremities. On the contrary, superficial sensation was impaired slightly in the left half of her body excluding face. The results of the psychological examinations, including Cornell Medical Index, manifest anxiety scale, Yatabe-Guilford personality inventory test, Rorschach test, Bender visual motor gestalt test and Tanaka-Binet test, revealed that her mental function is poor in general and immature socially. Being defective in intelligence (IQ was 73) and powerless to control her emotion, she could not cope with her intense anxiety about her physical state, and con- Fig. 1 : Skin lesion in the neck and left temporal area. 265 Pseudoxanthoma Elasticum Fig. 3: Optic fundi, right. Abnormal striae are noted among the blood vessels (arrows), Some of them Seem to be radiating from the disc. Fig. 2: Skin lesion in the left lateral neck, magnified. Small perforations of irregular shape are scattered among the papules. 4 & - f t F - R s F - A A , - A a n . A , & A & . - z9-m # wlf---+ G A . Aw4w--+43-A# -&-A, - R -0,- A .*zc + - A A t & F . G A - A A A + V W - 8 P \d...uvrr**hh % h QlI 1I . C Fig. 4: EEG. Background activity IS irregular, and moderate to high voltage theta bursts are observed frequently. 266 K. Goto Fig. 5 : Arch aortogram. Wall of the aorta and proximal portions of its main branches are smooth. Left common carotid artery is slender and both of the vertebral arteries are enlarged. The right coronary artery is small and seems to be somewhat sclerotic. Pseudoxanthoma Elasticum 267 Fig. 6 : Left common carotid angiogram, lateral projection. The left internal carotid artery is extensively narrowed from its origin and is completely obliterated at the ba.se of the skull (arrows). The external carotid artery and its branches are well opacified. 268 K. Goto Fig. 7 Figs. 7 and 8. Left vertebral angiogram, lateral and Towne projection. Tortuosity and dilatation of the vertebrobasilar arterial system is prominent. There are aneurysmal dilatation at the tip of the basilar artery and at the proximal portion of the ophthalmic artery (arrows). Pseudoxanthoma Elasticum Fig. 8 269 270 K. Goto Fig. 9: Right common carotid angiograrn, frontal projection. The proximal portions of the anterior and middle cerebral arteries are highly tortuous. The left anterior cerebral artery is also opacified via anterior communicating artery. Pseudoxanthoma Elasticum sequently observable tendency to escape from actualities in her attitude seemed to be formed. The EEGs recorded repeatedly showed an irregular background activity with a few alpha rhythm and frequent high voltage theta wave bursts of 5-6 cps rhythm which predominated in central, frontal and parietal areas. No definite spikes nor laterality were observed (Fig. 4). EKG showed ST-T depression in V, leads suggesting the myocardial ischemia in the lateral wall of the left ventricle. Retrograde aortography showed no abnormality of the aorta itself and no stenotic change at the origin of the cerebral arteries. The left common carotid artery was slender, on the contrary both of the vertebral arteries were dilated. The right coronary artery was small and seemed to be somewhat sclerotic (Fig. 5). The cerebral angiography revealed complete occlusion of the left internal carotid Fig. 11: Skin lesion of the neck. Hematoxylin and eosin stain X.560. Foreign body giant cells and epithelioid cells are observed among the round cells infiltrating at the bottom of a microsinus. 27 1 Fig. 10: Skin lesion of the neck. Van Gieson elastica stain x 142. There is prominent increase of the degenerated elastic fibers in the dermis. Fig. 12: Cross section of the superficial temporal artery. Van Gieson elastica stain ~ 9 8 Narrowing . of the vascular lumen is brought about by the thickening of the internal elastic lamella and the hyperplasia of the muscular coat in the media. 272 K. Goto artery in its extracranial portion. The left middle cerebral artery was visualized via enlarged basilar artery and posterior communicating artery, and left anterior cerebral artery via anterior communicating artery. The tortuosity and caliber irregularity of the cerebral arteries were prominent, especially in the supraclinoid portion of the internal carotid arteries, in the proximal portion of the middle and anterior cerebral arteries bilaterally and in the basilar artery. Aneurysmal dilatation was observed at the bifurcation of the basilar artery and at the beginning of the left ophthalmic artery. There was no obstruction of any visible vessels, vascular malformations and space taking lesions (Figs. 6, 7, 8 and 9). The results of the significant laboratory examinations were as follows: Complete blood count was normal. The erythrocyte sedimentation rate (ESR) was slightly accelerated (29/44 mm). CRP was positive three. Electrophoresis of the serum protein revealed moderate increase in gamma globulin fraction (28.6% ). Immunoelectrophoresis showed only slight increase in gamma G fraction (1960 mg/dl). Coomb’s test was negative. Biopsy of the skin lesion in the neck was performed. Van Gieson elastica stain showed marked increase of elastic fibers in the dermis. These elastic fibers were elongated, branched, fragmentated and granulated (Fig. 10). And in addition, the socalled microsinus formation and cell infiltration around it were noticed. The infiltrated cells were mostly round cells, and foreign body giant cells and epithelioid cells were also observed (Fig. 11). The skin lesion of this patient was diagnosed, from its macroscopic appearance and histological findings, as pseudoxanthoma elasticum accompanied by elastosis perforans. In con?ideration with these facts, the abnormal striae in the optic fundi were interpreted to be so-called angioid streaks. The histological examination of a small branch of the left superficial temporal artery showed marked narrowing of the vascular lumen. The prominent thickening of the vascular wall was brought about by the massive proliferation of the muscular coat in the media. The internal elastic lamella also showed thickening and irregularity. The intima and the external elastic lamella seemed to be almost normal. There was no cell infiltration in the vascular wall (Fig. 12). Her mother, her three sisters and one of her nieces were examined to ascertain the presence of pseudoxanthoma lasticum, angioid streaks and disturbance of peripheral circulation, but none of these abnormalities was found in any of them. The clinical course after admission was favorable in general: The predonisolon therapy was started from 30mg, which was gradually decreased to maintenanct dosis of 10 mg, and it was continued for several months. As a result, CRP turned negative, percentage of gamma globulin in the fractions of serum protein fell into normal range and acceleration of ESR disappeared. The administration of anticonvulsant drugs was started as soon as she entered the hospital and was continued from that time on. Her convulsive seizure was well controlled by 0.3 g of diphenylhydantion, 0.1 g of phenobarbital and 0.75 g of primidon given daily. For the skin and vascular lesion, 150 mg of tocopherol was given daily. For the last three years, the administration of anticonvalsants and tocopherol was continued, and she has been free of epileptic attacks and her skin lesion has shown tendency of healing. The ophthalmoscopic findings presented no obvious change and visual acuity remained normal. Her mental ability showed no marked deterioration. But “neurasthenic symptoms” lasted up to Pseudoxanthoma Elasticum date, and presently they are the cardinal symptoms of this patient. DISCUSSION Many authors considered that pseudoxanthoma elasticum is an avtosomal recessive hereditary disorder.2 lo But autosoma1 dominant mode of transmission and sporadic cases without detectable familial occurrence are also known.26 Though there are some arguments about the basic defect of this disease, it has been widely accepted that elastic fiber is primarily involved in the pathological process.1° l 3 li Reactive elastosis perforans is a rare condition which accompanies several genetic connective tissue disorders such as pseudoxanthoma elasticum, osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan syndrome and Rothmund-Thomson syndrome.ln l9 2o 21 30 33 And it is postulated to be a process of rejection of degenerated connective tissue by foreign body reactionz130 33 Some authors considered it to be an “autoimmune phenomenon”.’l Several abnormal laboratory findings which turned normal after predonisolon therapy and histological findings of the skin lesion of the present case seem to sustain such a hypothesis. The central nervous system (CNS) manifestations of this case are complicated, consisting of neurasthenic symptom, which is the earliest and most outstanding symptom, gradually progressive mental deterioration, multifocal neurological deficits and epilepsy. In reviewing the present history of this patient, it is to be noted that CNS disturbance developed just after papule of the skin and peripheral circulatory disturbance appeared. Therefore, the CNS manifestations of this patient seem to have close relationship with pseudoxanthoma elasticum. There are few reports in which detailed description was made on CNS manifesta- 21 3 tions of this disease, probably because the reports so far issued were mainly from dermatologists and ophthalmologists, and the CNS manifestations themselves are highly variable. But it is surprizing to know how many of the cases reported were accompanied by more or less prominent mental or psychic disturbances, such as psychoneur~sis,~~ 28 depre~sion,~ psychopat h ~ , psychosis,4 ~ 34 and mental deterioratiom31 Eddy and Farber,R reviewing 200 cases from the literature, found that, in this disease, “minor psychic disturbances (neurasthenia and minor memory loss) seemed to be quite common.” In a report by Carlborg et u Z . , ~ which is a detailed study of vascular changes on 29 cases of this disease, as many as 17 cases showed memory disturbance or forgetfulness, and four cases showed prominent nervousness. Minamilg reported on a 25-year-old male with pseudoxanthoma elasticum who seemed to be slightly dull mentally but otherwise normal on admission, developed severe psychic disturbance a few months later and was diagnosed as schizophrenia simplex. As is observed in the present case, Carlborg ef uL4 described the progressive nature of psychic symptoms as follows: “The mental symptoms, abnormal susceptibility to mental fatigue, and impaired ability to remember seemed to increase somewhat with time, as a result the patients usually are less and less able to cope with mentally tiring work”. Eddy and Farbers also found that 13 of 200 cases were accompanied by severe psychic disturbances. The occurrences of epilepsy in pseudoxanthoma elasticum is reported from time to time. Some of them were focal, but most of them were generalized type. Though there are not many cases with the descriptions of EEG findings, there seems to be no specific EEG abnormality in this disease.le 2i 32 Some authors reported that their cases 274 K. Goto showed normal EEG pattern.lG23 3i 3G The occurrence of paroxysmal activity in the EEG of the patients with pseudoxanthoma elasticum is not uncommon, even in cases without pronounced epileptic attacks.153‘ About the incidence of epilepsy in this disease, Conner and associates5 found three epileptics out of 106 cases of pseudoxanthoma elasticum. Eddy and Farber* also found only three epileptics in reviewing 200 cases of this disease. Therefore, they said that this fact “allows no conclusions as to its possible association with the disorder.” There are some cases with multiple focal neurological abnormalities, and repeated occurrence of which finally brings about highly desolated state of CNS function relatively at an early age. T a k a h a ~ h reported i~~ on a 53-year-old male who had transient right hemiparesis repeatedly when he was 30 years old, and during the last two years he had right hemiparesis, cerebellar ataxia and slight dementia. Sakai2i reported on a 35year-old woman who had, during the last two years, repeated attacks of disturbance in consciousness which was followed by transient speech disturbance, and finally developed right hemiparesis, dysarthria and dementia. The cerebral angiography demonstrated stenosis of both of the anterior cerebral arteries and marked tortuosity of bilateral middle cerebral arteries. Though there are many reports about the angiographic findings of the arteries of extremities in this disease, those referred to the cerebral vascular system are very rare. The cerebral angiography of a case reported by MinamiI9 revealed complete obstruction of the bilateral internal carotid arteries. RiosMontenegro et a1.25 reported on a 20-yearold male with proptosis and conjunctival vascular dilatation. Cerebral angiography revealed bilateral carotid occlusion at the base of the skull which is associated with bilateral carotid rete mirabile and right carotid-cavernous sinus fistula. No focal neurological abnormalities were observed in these cases. There are a few autopsy reports of the cases which showed progressive desolation of the CNS function. A 41-year-old male reported by Messis and BudzilovichlR showed “extensive mineralization of small arteries, arteriols and capillaries” and “patchy softening and diffuse demyelination” in almost all parts of the brain. And a 44-year-old female reported by Urbach and Wolfram35 presented multiple lesions in the internal capsules, pons and thalamus which showed various stages of softening. Cerebral vessels showed arteriosclerotic changes macroscopically. And histological examination on these vessels showed marked degenerative changes of the elastic fibers in the media and marked thinning and reduction of these degenerated fibers in the intima. And numbers of arteries showed various stages of stenotic changes. Those clinical and histopathological findings suggest that there is intimate relationship between CNS manifestations and vascular disorders in pseudoxanthoma elasticum. Though there are not many reports on histopathological findings of the vascular lesions in pseudoxanthoma elasticum, the most prominent changes were seen in the media of the arteries of extremities as well as that of the brain in the reported cases such as various aspects of degeneration of elastic fibers,l 2 2 2 x 35 deposition of collageand narnous materialIi or calcium’ Ii rowing of the vascular lumen which is brought about by marked hyperplasia of the muscular coat28 or fibrous tissue.1° In addition, there are some cases which showed thickening, fragmentation and calcium deposition of the internal elastic lamella of the cerebral arteries.’ 22 35 But there are almost no change in the intima Pseudoxanthoma Elasticum and external elastic lamella in most cases. The existence of inflammatory reaction in the vascular wall has not been mentioned in the literature. The association of extensive arteriosclerotic changes and necrosis of the elastic tissue in the arteries of patients with pseudoxanthoma elasticum were observed by several a ~ t h o r s35. ~ Goodman,lo McKusick17 and Robertson26 pointed out that severe generalized arteriosclerosis occurred in patients with pseudoxanthoma elasticum at an early age. The association of hypertension with pseudoxanthoma elasticum is quite common among the patients of 4 0 years and over. Eddy and FarberX found that nearly onefourth of 200 cases reviewed by them were hypertensive in varying degrees. This combination is not rare in young adults and it is sometimes observed even in little children.23 Though the pathomechanism of hypertension is obscure in most cases with this disease, it is ascribed in some cases to the pseudoxanthoma elasticum type vascular disease of renal vessels17 and angioma of kidney.g The combination of fragility of vascular wall brought about by connective tissue degeneration with hypertension seems to increase the risk of hemorrhage in patients with pseudoxanthoma elasticum. Relatively frequent sites of hemorrhage are gastrointestinal tract, urinary tract, nasal cavity and eye ground as well as CNS. Broustet and Bricaud3 reported on a 42-year-old female who developed malignant hypertension followed by left hemiplegia in the course of this disease. Carlborg e t d 4 reported on two cases of pseudoxanthoma elasticum with hypertension. One of them died of cerebellar hemorrhage and the other had repeated cerebral hemorrhage. Prick24 reported on a case of pseudoxanthoma elasticum with hypertension who died of pontine hemorrhage. The occurrence of aneurysm of cerebral 27 5 arteries in this disease is not so rare, and this sometimes causes CNS disorders. Dkon7 reported on a 29-year-old female with subclinoid berry aneurysm which caused subarachnoid hemorrhages and oculomotor and abducens nerve palsy. Scheie and Hoganz9 reported on two cases of carotid aneurysm, and added that one of them caused subarachnoid hemorrhage. Subarachnoid hemorrhage is said to be one of the main causes of death in this disease.17 In the present case, increased blood flow via vertebrobasilar arterial system, which is caused by the obstruction of the left internal carotid artery, and the degenerative process of arterial wall seem to have brought about prominent sclerotic change in this arterial system and aneurysmal dilatation of the basilar tip and proximal portion of the left ophthalmic artery. Thus, various CNS manifestations seen in pseudoxanthoma elasticum are thought to be closely related to the involvement of the cerebral arteries. Among them, “neurasthenic syndrome” seems to be the initial symptoms. This reminds us of the earliest symptom of the cerebral arteriosclerosis. Carlborg et ~ l . in, ~their extensive studies on pulse wave and histological changes about the arteries of extremities, pointed out that marked disturbance of the pulse wave is brought about by the degeneration of elastic substance in the vascular wall even though there were no stricture producing lesion. It may reasonably be assumed that neurasthenic syndrome is the earliest manifestation reflecting the existence of trophic disturbance of CNS. The progressive mental deterioration seems to be corresponding to the progression of cerebrovascular insufficiency. And repeated occurrence of the cerebrovascular accidents in the course of the disease often promotes much the desolation of C N S function relatively at an earlier age. The importance of psychopathological care and 27 6 K. Goto support to those patients with restricted mental ability should be recognized, because they seem to have a greater tendency to develop social maladaptation. SUMMARY A 24-year-old female with typical pseudoxanthoma elasticum of the skin, angioid streaks of the optic fundi and cardiovascular involvement developed neurasthenic symptoms, epilepsy, progressive mental deterioration and focal neurological deficits. Cerebral angiography revealed marked generalized arteriosclerotic change and occlusion of the left internal carotid artery. The literature of pseudoxanthoma elasticum is reviewed with special reference to central nervous system (CNS) manifestations. T h e possible role of the involvement of cerebral arteries in the genesis of CNS manifestations is discussed. And the importance of neurasthenic syndrome as an initial sign, which suggests that CNS involvement has already started in this disease, is stressed. ACKNOWLEDGMENTS I thank Dr. Koji Fuchi, who did a histological examination of the skin lesion, and Dr. Hirotoshi Umezaki and Dr. Tetsuo Inokuchi, who reviewed the manuscript and offered judicious advices. REFERENCES Bardsley, J. L. and Koehler, R.: Pseudoxanthoma elasticum: Angiographic manifestations in abdominal vessels, Radiology, 93: 559-562, 1969. Berlyne, G. M. and Manc, M. B.: Pseudoxanthoma elasticpm, Lancet, 1: 77-80, 1960. Broustet, P. and Bricqud, P.: Elastorrhexie et hypertension artCrielle maligne, Bull SOC Franc Dermatol Syphil, 69: 624-625. 4 Carlborg, U., Ejrup, B., Gronblad, E. and Lund, F.: Vascular studies in pseudoxanthoma elasticum and angioid streaks, Acta Med Scand, 350: 1-84, 1959. 5 Conner, P. 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