Epilepsia, 40(4):467473, I999 Lippincotr Williams & Wilkins, Inc., Philadelphia 0 International League Against Epilepsy

Clinical Research

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.

CASE REPORT

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.

DISCUSSION

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

467

468 D. E. JACOME

TABLE 1. EDS characteristics

Type Clinical features Inheritance Biochemical defect

I

11 111 IV

V VI

VII A, B

v11 c Vlll 1x

X Unc.

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 AD

XLR AR

AD

AR AD XLR

AR

Not known

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.

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EPILEPSY IN EHLERS-DANLOS SYNDROME 469

TABLE 2. Clinical material

Symptoms Signs

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 contralateral arm flexion before LOC. Numbness and tingling of hands and feet. Chronic tics of head rotation, mastication and coprolalia. Easy bruisability. Ritualistic head rotation movements before falling asleep

Dyslexia, decreased short-term memory, decreased hearing, hyperelastic skin and hypermobile joints. Lipomas of arms and R thigh. Generalized hyporeflexia, tics and mild choreic movements of limbs with action dystonia of hands. Extreme startle with absence of habituation to stimuli. Altitudinal visual defect 0s due to old retinal detachment

6 Extreme chronic fatigue without Speech hesitation due to residual (F, 35) hypersomnolence. History of L aphasia. Blepharoclonus in

temporal hematoma caused by ruptured cryptic AVM 18 years earlier. Manic-depressive behavior after bleed. CP S L S of diminished awareness R pronator drift associated to out-of-body experience. Thyroid tumor I2 years earlier. Easy bruisability and metrorrhagia. Whole-body tremors, nocturnal leg myoclonus. Chronic diarrhea. History of syncope

forceful and light eye closure associated with facial tremors. Arachnodactyly, flexible joints and scoliosis. L Babinski sign.

Test results

Skull radiographs: Occipital exostoses (Fig. 2) . Brain MRI: Left frontal subcortical signal hyperintensity in T,-weighted images next to caudate nucleus compatible with area of gliosis. EEG: Bilateral theta slowing. No epileptic discharges. SPECT: Normal. Chest radiographs: Lung hyperinflation and vertical heart

Skull radiographs: Occipital bony protuberance. Brain MRI: Partial Dandy Walker malformation (Fig. 5). EEG: Generalized sharp and slow wave complexes of frontal accentuation; normal during pseudoaeizures. Low serum magnesium, borderline low copper and ceruloplaamin levels. SPECT: Normal

MRA: Congenital hypoplasia basilar artery. Proximal stenosis R MCA and old infarct R external capsule. EEG: 6-H posterior dominant rhythm. Excessive intermixed slow activity while awake; generalized theta bursts. Swallowing evaluation: Poor oral skills and delayed swallowing initiation with pooling in vallecula and piriform sinus

the L hemisphere. EEG: Generalized sharp theta discharges. Ictal EEG: Left parietal focus, language area left hemisphere

Brain MRI: R parietal venous angioma. MRA: Bulbous appearance of the tip of basilar artery. No aneurysms. EEG: Mild slowing of background in theta range. EMG: complex prolonged polyphasic motor units in tested muscles of L arm, indicative of chronic reinnervation. Monoclonal gammopathy. Sural nerve biopsy: Axonal myelin loss. Muscle biopsy: Neurogenic atrophy and home ragged red fibers on H&E stains, hut normal biochemical muscle studies. E M muscle: Normal mitochondria. Blood immuno- phenotyping: Abnormal population of cytotoxic T cells. Bone marrow: No evidence of myeloma

perisylvian encephalomalacia (Fig. 7). Unable to demonstrate patency of posterior cerebral arteries. No acetylcholine receptor antibodies. Sleep studies: No sleep apnea. No HLA-DR2 antigen. EEG: Normal. EMG: Facial muscles and facial nerve repetitive electric stimulation normal

CT of the brain: Hypoplasia of

MRUMRA brain: Old L

TY Pe Others

IX (OHS) Able to self-abate szs by hyperextension of the neck 9 0 6 of the time. Poorly controlled with phenytoin and gdbapentin: well controlled with maximal doses of carbamazepine. Low serum copper; borderline low ceruloplasmin. COPD

IX (OHS) Congenital ventricular septa1 defect and history of SBE. Depression. Sexual impulse discontrol. Sz frequency reduction achieved with combination of carbamazepine and valproate; pseudoseizures improved with fluoxetine and psychotherapy

IV

111 (?)

1v

IV

History of multiple long-bone fractures with minor trauma and indifference to pain. Occasional CP szs with carbamazepine and phenytoin. Few grand ma1 seizures a year

Poor control of CP szs with multiple AEDs. Phenytoin and primidone well tolerated

Chronic multiple fluctuating tics, coprolalia. Peripheral neuropathy. Familial history of colonic polyposis, epilepsy, dyslexia, tics, and lipomatosis. Mother and brother died of ruptured thoracic congenital aneurysms. Early periodontitis and loss of teeth. Recurrent cystitis, Early retinal detachment. Jactatio capitis noctuma. Szs controlled with valporate and phenytoin combination

Daughter has hypermobile joints. One sister had infantile epilepsy. Seizures and affective illness well controlled with valproate

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470 D. E. JACOME

~

Case Symptom

7 (F, 68)

Severe, progressive pain of legs for 6 months. Grand ma1 szs for 7 years. Hand tremors. Chronic constipation, exertional dyspnea and wheezing. Easy bruisability. No history of stroke

TABLE 2. Continued

Signs Test results

Soft skin with visible veins. MRI brain: Old L perisylvian Flexible joints. Valgus encephalomalacia. Bilateral deformities of elbows. lacunar strokes, leukoaraiosis. Exquisitely tender calf muscles EMG: Complex prolonged on palpation. Blepharoclonus, polyphasic motor unit action tremors of hands. potentials on leg muscles. Decreased pinprick perception Small dispersed peroneal distal on feet CMAPs. Unable to obtain F

waves. Muscle biopsy: Type grouping. Sural nerve biopsy: Small myelinated axonal loss. Sedimentation rate: 41 mmh. EEG: Normal

Type Others

Unc. Hypertension, bronchial (111 or IV) asthma, COPD, chronic

urticaria. Family history of early-onset arthritis; brother had hip replacement at age 40. Szs well controlled with phenobarbital

AEDs, Antiepileptic drugs; AVM, arteriovenoua malformation; CMAP, compound muscle action potential; COPD, chronic obstructive pulmonary disease; CP szs, Complex partial seizures; CT, computed tomography; EDS, Ehlers-Danlos syndrome; EEG, electroencephalogram; EMG, electromyography; L. left; LOC, loss of consciousness; MCA, middle cerebral artery; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; OHS, occipital horn syndrome; OS, left eye; PAS, pain asymbolia; PSH, penventricular subependymal heterotopia; R, right; SBE, subacute bacterial endocarditis; SMA, supplementary motor area; SPECT, single photon emission computed tomography; Szs, seizures; Unc, Unclasified.

(SMA) origin because of their ictal tonic posturing of the arms, speech arrest, emission of sounds, and head devia- tion (13). Seizures arising from this area were repro- duced by Penfield and Jasper (14) on electrical cortical stimulation. The SMA occupies the medial surface of the cerebral hemisphere superior to the cingulate gyms and anterior to the motor area of the foot and leg; therefore, seizures arising from this area are difficult to record by

using surface EEG electrodes (13,14). Although lesions of the SMA may result in typical seizures, only case 1 of this series had a demonstrable lesion of the SMA (local- ized frontal lobe gliosis). The semiology and electroen- cephalography of SMA seizures was summarized in the classic monograph by Penfield and Jasper and in the historic papers by Penfield and Welch (14-16). To my knowledge, none of the patients of their series was di-

FIG. 2. Case 1. Skull radiographs. Occipital exostosis (occipital horn).

FIG. 3. Case 2. Coarse facies, redundant skin of forehead, wide nasal bridge, sparse eyebrows, steely hair.

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EPILEPSY IN EHLERS-DANLOS SYNDROME 4 71

FIG. 4. Case 2. Easily bruised. Subcutaneous hematoma of the leg after trivial trauma.

agnosed with EDS. Case 2 had mirror movements (imi- tation synkinesis). Mirror movements are an uncommon finding in children and adolescents and may result from focal lesions of the cerebral hemisphere or spinal cord, but are not typical of EDS or Dandy Walker malforma- tion (17,18).

Patient 3 had pain asymbolia (PAS). Two earlier pa- tients with EDS and PAS were reported by Silverman and Gilden (19). PAS, or congenital indifference to pain,

must be distinguished from congenital insensitivity to pain caused by hereditary sensory peripheral neuropathy. Individuals with PAS perceive pain normally but are missing the emotional and motor (withdrawal) cerebral components of pain (20). PAS is currently understood as a sensorilimbic disconnection syndrome ( 2 I ) . Berthier et al. (22) reported a patient with bilateral sensory seizures and PAS due to a tumor of the right insula. Case 3 did not have insular lesions. The affective illness of patient 6 was probably the result of her old intracranial bleed, which involved the left hemisphere (23). Her protracted fatigue can be explained on basis of depression and medication side effects, or perhaps as a late sequella of her intracerebral hemorrhage, because otherwise she had no signs of the cardiovascular or pulmonary disease that sometimes complicates EDS (24). Also of interest is pa- tient 4’s crossed distal right arm and left leg develop- mental hypotrophy in the presence of congenital left hemispheric atrophy. It is logical to assume that her crossed-limb acrodysplasia was a congenital expression of her EDS mediated through the central nervous system. Finally, patient 5’s Tourette syndrome, familial intestinal polyposis, and familial lipomatosis were unrelated to EDS, in contradistinction to his dyslexia, seizures, and venous angioma. Although peripheral neuropathy may be a manifestation of EDS, he had immunoglobulin M (IGM) monoclonal gammopathy and familial lipomato- sis, both established cases of peripheral neuropathy (25,26). Nocturnal oscillations of the head, ‘‘nocturnal head banging,” or jactatio capitis nocturna, refers to the frequent nocturnal rotational head movements that occur

FIG. 5. Case 2. Partial Dandy Walker malformation. Brain MRI, T,-weighted im- age. Ascended hypoplastic cerebellum and “open” fourth ventricle in the absence of hydrocephalus.

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472 D. E. JACOME

before falling asleep. Jactatio capitis is observed in chil- dren with behavioral disorders after head trauma, or as a parasomnia (27). It is unclear if the jactatio capitis of patient 5 was part of his Tourette syndrome or if it rep- resented a parasomnia, because overnight sleep studies were not performed.

Because case 3 had basilar artery hypoplasia, case 2, Dandy Walker malformation, case 1 was able to abate his seizures by hyperextending his neck, and because the previously reported case by Thomas et al. (8) had agen- esis of the corpus callosum, one could legitimately ask whether in certain patients with EDS, prenatal insuffi- ciency of the vertebrobasilar arterial system is present, resulting i n developmental arrest or malformations of anatomic structures supplied by this system. In addition, a vascular disturbance of the posterior circulation could be potentially aggravated by neck hyperextension be- yond physiologic limits during delivery in someone with lax connective tissue. This excessive flexibility of the neck would allow stretching or compression to already abnormal vertebral arteries due to EDS.

The pathogenesis of the neurologic manifestations of EDS is based on the genetic and biochemical anomalies

FIG. 6. Case 4. Congenital atrophy of the left leg.

Epilc,p\ia. Vol. 40. N o . 4. 1999

FIG. 7. Case 6. MRI of the brain, T,-weighted image. Perisyl- vian encephalomalacia from old hemorrhage.

of the connective tissue in this disorder. A disruption in the link between the extracellular matrix and cytoskele- ton causes aberrations in cellular migration during de- velopment. This disruption may result in various con- genital malformations of the vessels and the brain paren- chyma, including cortical dysgenesis, which at times is difficult to detect with current conventional neuroimag- ing techniques (28-32). Any of these lesions may cause epilepsy in individuals with EDS. Finally, subjects with EDS and epilepsy may have normal interictal EEG?, as was the case in some of the patients in this series (cases 6 and 7), or show nonspecific paroxysmal activity (cases 1, 4, and 5). Therefore, prolonged EEG monitoring with ictal recordings is necessary in patients with EDS and episodic behavioral disorders whose baseline EEG trac- ings are normal or contain nonspecific abnormalities.

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