Epilepsy in Menkes Disease: Analysis of Clinical Stages

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1 Epilepsia, 47(2): , 2006 Blackwell Publishing, Inc. C 2006 International League Against Epilepsy Epilepsy in Menkes Disease: Analysis of Clinical Stages Nadia Bahi-Buisson, Anna Kaminska, Rima Nabbout, Christine Barnerias, Isabelle Desguerre, Pascale De Lonlay, Michele Mayer, Perrine Plouin, Olivier Dulac, and Catherine Chiron Service de Maladies métaboliques et Neurologie Pédiatrique, Hôpital Necker Enfants Malades; 2 Inserm U663, Paris, F France; and University Rene Descartes, Paris V, F-75005, France; Service de Neurophysiologie and Service de Neuropédiatrie, Hôpital Cochin St Vincent de Paul; and Service de Neurophysiologie Hôpital Necker Enfants Malades, Paris, France Summary: Purpose: Epilepsy is one of the main features of Menkes disease (MD), although it is not described in depth. To determine the spectrum of epilepsy, we studied its main characteristics. Methods: Based on clinical charts, we retrospectively analyzed the evolution of electroclinical features of 12 patients with confirmed MD. Results: Epilepsy could be divided into three periods: (a) an early stage (median age, 3 months), characterized by focal clonic status epilepticus, usually triggered by fever (10 patients). Ictal EEG showed runs of slow spike waves and slow waves in the posterior regions, and interictal EEG multifocal and polymorphic slow waves (three cases), or mixed slow spike waves and slow waves (seven cases). Partial seizure control was obtained in nine patients during 5.9 months; (b) an intermediate stage (median age, 10 months) with intractable infantile spasms (11 patients) in which interictal EEG demonstrated modified hypsarrhythmia (seven cases), diffuse irregular slow waves and spike waves (four cases). Six patients died at the median age of 15 months; and (c) a late stage in the six remaining patients (median age, 25 months), with multifocal seizures, tonic spasms, and myoclonus in four patients, whereas two patients became seizure free. Interictal EEG showed multifocal high-amplitude activity, mixed with irregular slow waves in all six cases. These patients died at the median age of 3.6 years. Conclusions: Based on a relatively large series of MD patients with a quite prolonged survival, we individualized three successive periods in the course of epilepsy: early focal status, then infantile spasms, and then myoclonic and multifocal epilepsy after age 2 years. Key Words: Menkes disease Copper transport deficiency Cerebral degeneration Epilepsy Infantile spasms Basal ganglia. Menkes disease (MD; MIM ) is a rare X-linked recessive disorder with a primary generalized defect in copper transport (1,2). It is characterized by progressive cerebral degeneration with psychomotor deterioration and seizures, connective tissue alteration with hypopigmentation of skin and hair, and recurrent episodes of hypothermia with failure to thrive (3,4). Neuronal degeneration predominates in cerebral and cerebellar cortices and in the basal ganglia (5,6). Serum copper and ceruloplasmin levels are low, whereas copper accumulates in the duodenal mucosa and cultured fibroblasts (7 10). Menkes disease is related to the loss of a coppertransporting adenosine triphosphatase (ATPase; ATP7A) involved in the export of dietary copper from the gastrointestinal tract and its transport into organelles (11,12). It results in a copper deficiency and subsequent impairment Accepted September 23, Address correspondence and reprint requests to Dr. N. Bahi-Buisson at Necker Enfants Malades Hospital, Department of Pediatric Neurology, 149 rue de Sèvres, Paris cedex 15, France. nadia.bahibuisson@nck.ap-hop-paris.fr of activity of multiple copper-dependent enzymes, including lysyl oxidase, cytochrome c oxidase, dopamine β- hydroxylase, tyrosinase, and superoxide dismutase, which contribute to the clinical features of Menkes disease (7,8,13). In his original report, Menkes described EEG features of Menkes disease as early multifocal spikes later becoming diffuse (1,14,15). Myoclonus is supposed to be a usual seizure type, and two case reports recently described infantile spasms in patients with Menkes disease (16,17). However, electroclinical studies are very scarce, although epilepsy is a frequent and early feature in this disorder (1,14,15). To determine the spectrum of electroclinical features and their course, we retrospectively studied 12 patients with Menkes disease. PATIENTS AND METHODS All the patients identified as having Menkes disease in our pediatric unit of neurology and metabolism over a period of 20 years ( ) were included in this study. 380

2 EPILEPSY IN MENKES DISEASE 381 They were 12 boys. Epilepsy was the presenting symptom when they were referred to us. They all fulfilled the following clinical and biologic diagnosis criteria of Menkes disease (18): progressive neurologic disease with marked hypotonia and poor eye contact, pathognomonic hair abnormalities consisting of pili torti, feeding difficulties with failure to thrive, and low plasma copper and serum ceruloplasmin levels. A high 64 Cu uptake into cultured fibroblasts was also present in the four cases explored. The hospital records of all children were retrospectively reviewed. Data used for the characterization of epilepsy were the history sustained from parents and caretakers, with specific attention to incidence, seizure types [according to International League Against Epilepsy (ILAE) 89], severity of epilepsy determined by daily seizures, more than three different types of seizures, status epilepticus, and a history of refractory epilepsy. We also recorded age and circumstances of onset of seizures. Ten-channel EEG records during >2 h, including ictal and interictal recording, were performed in all cases, and video-eeg monitoring was available in three patients. Analysis of EEGs was performed with a specific attention to interictal abnormalities, electrographic seizures, and background activity during wakefulness, drowsiness, and sleep. RESULTS All patients were referred to our institution for repeated seizures or status epilepticus. Postural delay and hypotonia had been noticed before the onset of seizures in all cases. However, the diagnostic of Menkes disease had never been suggested before referral. In addition, neither biologic investigation nor EEG recording had been performed before the onset of epilepsy. The age at onset of seizures ranged from 2.5 to 8 months (mean, 3.5 months; median, 3 months). At this age, patients were admitted for partial clonic status epilepticus (10 of 12). Two patients, aged 6 and 8 months, were referred for infantile spasms without any previous history of focal clonic seizures. Based on clinical charts, the history of epilepsy could be divided into three periods: an early stage characterized by focal clonic seizures often evolving into status epilepticus, an intermediate stage with epileptic spasms, and a late stage with the occurrence of multifocal seizures, tonic spasms, and myoclonus. Early status epilepticus At onset, 10 patients had status epilepticus with focal clonic seizures affecting one side of the body, or both sides alternately. These seizures were extremely severe and lasted from 1.5 to 7 days (3 days ± 1.9). This status was refractory to all antiepileptic drugs (AEDs) including clonazepam (CZP) and phenytoin (PHT). Ipsilateral hemiplegia was associated, either transiently (one case) or permanently (three cases). At this stage, we did not observe any other type of seizures (tonic, atonic, or spasms). Ictal EEG showed runs of regular, nearly rhythmic, high-amplitude (>200 μv) discharges of slow spike-andwaves and slow-waves (delta to theta) activity with focal distribution usually with predominance over the posterior regions, and epileptiform discharges (spikes and sharp waves) ranging from moderate to low amplitude. These discharges were unilateral (seven of 10) or bilateral (three of 10), affecting the posterior regions, either temporal (one case), or occipital (two cases), or temporooccipital (seven cases) (Fig. 1A). In all cases, we could identify an acute infectious event triggering the first seizures: fever greater than 39 C (10 cases) associated with gastroenteritis (six of 10) or pneumopathy, (three of 10), or pyelonephritis (one of 10). This event was severe and led all children to be hospitalized for infectious disease associated with hypotonia. Seizures started between 24 h and 3 days after the onset of the infectious disease and after the control of fever and the infectious process with antibiotics. This initial status epilepticus was a unique episode; none of our patients more exhibited status epilepticus or severe repeated seizures. A significant reduction of seizure frequency (less than once a month) was obtained for nine patients. This period of low seizure frequency ranged from 3 to 10 months (mean, 5.9 months). Seizures during this period were reported as focal clonic (two cases), generalized tonic (three cases), or consisting of atypical absences (one case). The first interictal EEG was performed at the mean age of 4.3 months, a few days after the end of the status epilepticus. It showed polymorphic slow waves (theta delta activity) in five cases, mixed with slow spikes and waves, and spikes (in seven cases). These EEG abnormalities were multifocal, mostly localized in the posterior regions (Fig. 1B). The background activity was either too slow and sleep spindles were rare (four cases) or absent (six cases). CT/MRI findings All patients underwent brain imaging, MRI (six cases) or CT scan (six cases) at the time of diagnosis (between ages 3 and 8 months; median, 4 months). Global cerebral atrophy was observed in nine cases, and cerebellar atrophy, in six cases. Focal lesions were noted in four cases, affecting the temporooccipital (three cases) or frontoparietal (one case) lobes. These focal and posterior lesions were consistent with ischemic damage, given the hypersignal on T 1 -weighted and hyposignal in T 2 -weighted sequences. Increased signal of the white matter on T 2 was observed in the oldest patient having had MRI (8 months), suggesting delayed myelination. We did not observe any abnormalities of the basal ganglia.

3 382 N. BAHI-BUISSON ET AL. FIG. 1. EEG recording during the early stage of status epilepticus (5 months). A: Ictal EEG: Subclinical occipital seizure: rhythmic theta activity on both occipital areas lasting 2 to 3 min; no clinical change. B: Interictal EEG: slow activity (occipital delta theta waves), no focus of spikes. Late-onset infantile spasms All patients had epileptic spasms in clusters at the mean age of 9.5 months (median, 10 months), except one who died at age 8 months and had never had infantile spasms before his death. In all patients but two, focal seizures had preceded the spasms. The free interval between the end of the initial status epilepticus and the onset of infantile spasms ranged from 3 to 10 months (mean, 5.9 months). In all cases, patients were immediately referred to the hospital when spasms appeared, and we did not observe any treatment lag. Spasms were flexor (one of 11), extensor (five of 11), or mixed (five of 11). In addition to spasms at this second stage, eight patients also had generalized clonic (three) or tonic (three) or myoclonic (two) seizures that were easily controlled with antiepileptic drugs (AEDs). Ictal EEG was obtained in five cases, showing a typical pattern of spasms that consisted of a high-voltage slow wave superimposed by a burst of fast rhythms (Fig. 2A). Interictal EEG at the onset of spasms showed complete disappearance of background activity (basal activity and sleep spindles), replaced by multifocal high-amplitude

4 EPILEPSY IN MENKES DISEASE 383 FIG. 2. EEG recording during the intermediate stage of infantile spasms (12 months). A: Ictal EEG: epileptic spasm (arrow) associated with a generalized complex of slow waves and fast rhythms; return to hypsarrhythmic pattern. B: Interictal EEG: Multifocal high-amplitude and polymorphic activity, mixed with irregular slow waves (modified hypsarrhythmia). and polymorphic activity, mixed with irregular slow waves (modified hypsarrhythmia) in seven of 11 cases (Fig. 2B), diffuse spikes and spikes-and-waves over both hemispheres in two cases, and diffuse irregular delta slow waves in two cases. Epileptic spasms were extremely resistant to all AEDs administered, including benzodiazepines (BZDs), valproate (VPA), vigabatrin (VGB), and phenobarbital (PB). Steroids were tried in one case, without efficacy. The ketogenic diet was not tried.

5 384 N. BAHI-BUISSON ET AL. Course Six patients died before age 18 months (median, 15 months). For the remaining six patients, only one was still alive at age 34 months, and five died at the mean age of 38 months (median, 43 months). Among these six patients, two were seizure free, and in four, multifocal epilepsy with jerks developed at a median age of 25 months (between 20 and 28 months). Seizures were polymorphic, combining brief tonic seizures and bilateral myoclonic jerks. These myoclonic jerks could be either spontaneous or could be triggered by voluntary movement or various stimuli (touch, pain, sound, or light). In two patients, isolated spasms were also observed and persisted after age 24 months. Ictal EEG recording of myoclonic jerks and tonic spasms was obtained in two cases (Fig. 3A). Interictal EEG showed multifocal high-amplitude and polymorphic activity mixed with irregular slow waves in tracings in all cases (Fig. 3B). For the two seizure-free patients, no EEG could be recorded. DISCUSSION We describe a three-step epilepsy course in this series of 12 Menkes patients, characterized by prolonged focal FIG. 3. EEG recording during the late stage of multifocal epilepsy (36 months). A: Ictal EEG: Myoclonic jerk (arrow) followed by bilateral SW lasting 10 s, associated with left arm clonic movements. B: Interictal EEG: rare occipital background activity associated with slow waves and rare occipital spikes. Calibration: 50 mv, 1 s.

6 EPILEPSY IN MENKES DISEASE 385 FIG. 4. Evolution of epilepsy in 12 patients with Menkes disease. This figure summarizes the course of epilepsy of 12 patients indicated with the numbers from 1 to 12 on the left. Epilepsy periods are designed by different colors: black for early status epilepticus, vertical stripe for infantile spasms, and horizontal stripe for late multifocal epilepsy. The duration of each period of the epilepsy is indicated in months. clonic seizures from early infancy, followed by late-onset infantile spasms, and then polymorphic seizures including myoclonus after age 2 years, if alive. Epilepsy is one of the main features of Menkes disease; it is reported in all our cases. In the original report, epilepsy is defined as two-step evolution epilepsy (1,14,15). In our relatively large series for such a rare disease, we could describe more precisely these two steps through ictal EEG and individualize a third step in the patients who survived longer than in previous reports (Fig. 4). The first seizures usually reveal the disease, although children already had most of the clinical features of Menkes disease. In the literature, a unique patient underwent EEG before epilepsy onset; it was normal (14). In our series, first seizures frequently arise during infectious diseases, they are extremely severe, evolving to status epilepticus, and associated with sudden deterioration of the clinical condition, in children who had previously never been brought to hospital. These characteristics of severity and infectious triggering have not been previously identified. The second step is characterized by infantile spasms, which occur later (mean, 9.5 months) than is usual in West syndrome. Infantile spasms were very recently recognized in four patients with Menkes disease (16,17). By using polygraphic EEG recording, we could demonstrate that this seizure type was present in all the patients of our series. We suggest that infantile spasms could have been underestimated in the previous reports (14). The third stage of epilepsy can be observed only when children survive after the age of 2 years. Spasms are progressively replaced by polymorphic seizures with jerks, whereas the multifocal characteristics of the epilepsy become more apparent. Polygraphic EEG recording showed that most of these jerks were myoclonia. Although poorly described in the literature, myoclonus can therefore also be considered a rather usual seizure type in the course of Menkes disease. This myoclonus has characteristics of cortical origin because it can be spontaneous or action or reflex induced (19). Epilepsy is a frequent symptom in metabolic diseases, although it remains incompletely described in some of them, particularly regarding EEG features. Myoclonus is considered the usual seizure type and often leads to metabolic investigations in newborns and infants. Infantile spasms are uncommonly reported in inborn metabolic disorders, but probably are underestimated because of the lack of polygraphic EEG recording. They are associated with a few conditions such as phenylketonuria (20), pyruvate dehydrogenase complex deficiency (21), or mitochondrial disease (22,23). Early clonic seizures with hypotonia can reveal biotinidase deficiency (24). Polymorphic seizures are also associated with mitochondrial disorders such as infantile spasms (NARP) (22,23), progressive myoclonus epilepsy (MERFF), or focal status epilepticus (MELAS) (25). Myoclonus is usually observed in progressive degenerative encephalopathy, such as Unverricht Lundborg and Lafora diseases (19). However, clinical and biologic features associated with epilepsy are usually different from Menkes disease and are helpful for the diagnosis.

7 386 N. BAHI-BUISSON ET AL. Pathophysiologic mechanisms of epilepsy in Menkes disease remain unknown, but they are likely related to the copper deficiency. It results in an impairment of lysyl oxidase, considered as the primary cause of the abnormal intracranial vessel structures, and superoxide dismutase and cytochrome c oxidase (COX) deficiencies that are involved in energetic production (26 29). Progressive vascular changes secondary to lysyl oxidase deficiency predispose to thrombosis and deficient blood supply to the developing brain (2,30,31). We hypothesize that the acute cortical damage causing the initial status epilepticus might result from the combination of vascular dysfunction and a defect of energy production, triggered by the acute metabolic stress secondary to the severe infection (6). Regarding infantile spasms, many authors focused on subcortical structures as the primary mechanisms for generating spasms (32 34). In Menkes disease, the neuropathologic changes, characterized by neuronal degeneration, predominate in basal ganglia, mostly in thalamic nuclei (5,6). Refractory infantile spasms are known to evolve frequently to Lennox Gastaut syndrome with a progressive synchronization of paroxysmal activity of the two hemispheres that is sustained by normal myelination at this age. Both are lacking in Menkes disease (35,36), thus leading to multifocal epilepsy (33). Finally, the cortical myoclonus could be related with the progressive cortical degeneration described in Menkes disease, that leads to the deafferentation of cortical neurons of the motor strip (5,6). CONCLUSION Based on a relatively large series of Menkes patients with a quite prolonged survival, we individualized three successive periods in the course of epilepsy: early focal status, then infantile spasms, and then myoclonic and multifocal epilepsy after age 2 years. REFERENCES 1. Menkes JH. Kinky hair disease. 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