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Epilepsia, 40(4):467473, I999 Lippincotr Williams & Wilkins, Inc., Philadelphia 0 International League Against Epilepsy
Epilepsy in Ehlers-Danlos Syndrome
Daniel E. Jacome
Department of Medicine, Franklin Medical Center, Greenfield, Massachusetts, and Section of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.
Summary: Purpose: Ehlers-Danlos syndrome (EDS) is a complex hereditary connective tissue disorder infrequently re- ported in association with epilepsy. Seven patients with ages ranging from 28 to 70 years with EDS and epilepsy are de- scribed.
Methods: Case review of clinical and diagnostic data. Results: Two patients had occipital horn syndrome (EDS
type IX) and partial seizures of probable supplementary motor area origin. Of these two, one had an area of frontal gliosis and was able to abate his seizures by hyperextending his neck; the other had a Dandy Walker malformation and also had pseudo- seizures. The third patient of the series had complex partial seizures, pain asymbolia, and basilar artery hypoplasia. The fourth had ictal aphasia, left hemispheric hypotrophy, and distal
right arm and left leg atrophy. The fifth patient had focal sei- zures, a venous parietal angioma, hyperekplexia, nocturnal head oscillations Cjactatio capitis nocturna), monoclonal gam- mopathy-associated neuropathy, and Tourette syndrome. The sixth had affective illness, chronic fatigue, and complex partial seizures with autoscopic phenomena after intracranial bleed. The seventh patient had a previous stroke, peripheral neurop- athy, and grand ma1 seizures.
Conclusions: EDS may be accompanied by congenital or acquired central nervous system disorders and epilepsy. Addi- tional neurologic conditions that are unrelated to EDS may be present. Key Words: Epilepsy-Ehlers-Danlos syndrome- Hereditary disorders-Occipital horn syndrome-Supplemen- tary motor area.
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders character- ized clinically by variable degrees of joint hypermobility, skin fragility, skin hyperextensibility, and excessive bruising (1). Ten different categories are recognized that differ in their predominant features (i.e., dental or ocular involvement, clotting disturbance), type of inheritance, and underlying biochemical abnormalities (Table 1). This syndrome was named after the works of Ehlers in Germany in 1901 and of Danlos in France in 1908, who described patients with extensible skin and easy bruising (2) . Related syndromes are osteogenesis imperfecta, al- kaptonuria, homocystinuria, Marfan, and Menkes syn- dromes (3). EDS is underrecognized by neurologists be- cause many of these patients have milder clinical pre- sentations and do not seek medical care, or are seen by physicians in different specialties. Seven patients with EDS and epilepsy are described.
Accepted October 13, 1998. Address correspondence and reprint requests to Dr. D. E. Jacome at
Poster presentation at the annual meeting of the American Epilepsy One Burnham Street, Suite 2, Turners Falls, MA 01376, U.S.A.
Society (AES), December 8, 1997, Boston, Massachusetts.
The patients were seen in a rural practice setting. They have been personally followed up by the author for a minimum of 2 years and were examined on multiple occasions. Four of the patients were referred for neuro- logic consultations because of their epilepsy, two be- cause of symptoms of peripheral neuropathy, and the remaining patient because of extreme fatigue. They were diagnosed with EDS on initial evaluation based on their findings of joint hypermobility, skin hyperextensibility (Fig. 1), skin fragility, musculoskeletal dysplasia, and family history. Two cases of occipital horn syndrome (OHS) were diagnosed because of their typical occipital exostosis. Details of their clinical findings and test re- sults are provided in Table 2.
The neurologic manifestations of EDS include cere- brovascular disease, peripheral neuropathy, plexopathy, periventricular subependymal heterotopia (PSH), and epilepsy. Cerebrovascular disease in the form of intra- cranial aneurysms, subarachnoid hemorrhage, and spon- taneous arterial dissection resulting from collagen type
468 D. E. JACOME
TABLE 1. EDS characteristics
Type Clinical features Inheritance Biochemical defect
11 111 IV
VII A, B
v11 c Vlll 1x
Soft hyperextensible skin: easy bruising, thin atrophic
Similar to EDS I but less severe Soft skin, joint hypermobility Thin, translucent akin with visible veins; easy bruising;
scars, hypermobile joints, varicose veins, classic form
absence of skin and joint extensibility: arterial, bowel, and uterine rupture
Similar to EDS I1 Muscle hypotonia: scoliosis; joint laxity, hyperextensible
Congenital hip dislocation; severe joint hypermobility; skin, ocular anomalies
soft skin with normal scarring
Soft, lax, fragile skin. Human form of dermatosparaxis Periodontitis; soft, lax skin Soft, extensible, lax skin; bladder diverticulae and rupture;
broad clavicles; occipital horns Similar to EDS 11: abnormal clotting
AD AD AD
AR AD XLR
Not known Not known Abnormal type I11 collagen synthesis, secretion or
structure; deletions and point mutations in COL3AI gene
Not known Lysyl hydroxylase deficiency: homozygous and compound
Deletion of exons from COLl Al (VIIA) and COLIA2 heterozygous mutations
(VIIB) that encode amino terminal propeptide cleavage sites
Procollagen N-proteinase deficiency Not known Abnormal copper utilization with defect in lysyl oxidase
Possible defect in fibronectin c
Joint hypermobility, skin hyperextensibility Lack of proa2 ( I ) collagen chains in some cases
AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recesqive. Modified from ref. 1, with permission.
111 deficiency, is typical of EDS type IV (4). Peripheral nerve disorders in EDS tend to be chronic, are often precipitated by trauma, and the patients exhibit conduc- tion block of electrical nerve impulses on electrophysi- ologic testing (5). Underlying hereditary neuropathy with susceptibility to pressure palsies ( tomaculous neuropa- thy) may be present (6). Epilepsy is rarely reported in EDS (7). Thomas et al. (8) described a 24-year-old woman with complex partial and right sensorimotor sei- zures. Her brain magnetic resonance imaging (MRI) showed PSH, agenesis of the posterior third of the corpus callosum, and mega cisterna magna. OHS is an X-linked recessive form of EDS diagnosed by the presence of
occipital exostosis (Figs. 2 and 3), obstructive uropathy, and chronic diarrhea, in addition to the typical features of EDS (9). OHS is caused by a defect in copper metabo- lism, which leads to lysyl oxidase deficiency and abnor- mal collagen (10). OHS closely resembles a mild adult variant of Menkes disease. In fact, OHS may be the result of a point mutation in the Menkes disease gene (1 1). Epilepsy may complicate OHS; a patient of Wakai et al. (12) with OHS and myopathy had recurrent sei- zures beginning at an early age.
Some clinical aspects exhibited by these patients de- serve specific commentary: Patients 1,2, and 5 had clini- cal seizures suggestive of supplementary motor area-
FIG. l . Case l . Hyperextensible skin.
Epilepsiu, Vol. 40. N o . 4, 1999
EPILEPSY IN EHLERS-DANLOS SYNDROME 469
TABLE 2. Clinical material
Grand ma1 szs in the past; auras of increased intestinal peristalsis or impending doom followed by sudden apnea, emission of loud sounds, abrupt elevation of the arms, and head turning before LOC. At other times, conscious but unable to speak (expressive aphasia).
Rare grand mal; episodes of sudden unresponsiveness, emission of sounds, and simultaneous elevation of arms with head turning. Pseudoseizures manifested by head rocking and chest banging with hands.
Grand ma1 ses during childhood. CP szs with confusion, motor automatisms and aphasia, or of head drop and confusion. Daytime hypersomnolence and L side weakness. Chronic urinary incontinence. Easy bruisability and indifference to pain. Frequent coughing episodes. Dysphagia
Palpable occipital protuberance, steely hair, frontal bossing, ocular slant, mild hypoplasia of R orbit, micrognathia, low implantation of thumbs. Hyperextensible soft skin, joint hypermobility, penguin gait with feet in eversion, mild midline frontal hypopigmenta- tion, and redundant interdigital akin (syndactyly) (Fig. I )
protuberance. Frontal bossing, soft hyperextensible skin, easy bruisability and subcutaneous hematoma formation. Short, wide fingers with small nails and ball fingertips. Steely hair, progeroid facies, redundant frontal skin, mild blue tinting of scleras, micrognathia. Mild spastic gait (Figs. 3, 4)
Nasdl/dysarthric speech with weakness of palate elevation, mild L hemiparesis with hyperreflexia, L Babinski. Asterixis and aprawic gait. Frontal bossing. Large head. Navicular palate. Soft hyperextensible skin
Palpable bony occipital
Moderate mental retardation.
4 Remote history of grand ma1 szs. Joint hypermobility, pedal (F, 28) CP szs of R hand and facial
numbness, expressive aphasia and falls without LOC. Brief szs every other day Babinski
dexterity, hypotrophic R hand and L leg (Fig, 6). L leg hyperactive reflexes and L
5 S (M, 69)
zs began at age 46. Sleepy and sweaty before szs. Grand mals or episodes of right arm elevation and tremors followed by cont