Short Communication

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Epilepsia Partialis Continua and Generalized Nonconvulsive Status Epilepticus during the Course of Argininemia: A Report on Two Cases D. Grioni1

F. Furlan2

F. Canonico3

R. Parini2

1 Child Neuropsychiatric Clinic, San Gerardo Hospital University of

Milan Bicocca, Monza, Italy 2 Center for Metabolic Diseases MBBM Foundation, San Gerardo Hospital, Monza, Italy 3 Neuroimaging Unit, San Gerardo Hospital University of Milan Bicocca, Monza, Italy

Address for correspondence D. Grioni, MD, Child Neuropsychiatric Clinic, San Gerardo Hospital, via Pergolesi 33 20052, Monza (MB), Italy (e-mail: [email protected]).

Abstract

Keywords

► argininemia ► epilepsia partialis continua ► status epilepticus ► urea cycle disorders ► levetiracetam ► valproic acid

Argininemia is a rare inherited disorder of the urea cycle because of a deficiency of the enzyme arginase I causing an increase of arginine and guanidino compounds in the blood, urine, and cerebrospinal fluid. The clinical picture is characterized by a mild cognitive dysfunction, progressive asymmetrical paraparesis, and seizures. Here, we describe two cases of argininemia where either epilepsia partialis continua (EPC) or nonconvulsive status epilepticus (NCSE) were the presenting manifestations of epilepsy. This is the first report of EPC in an urea cycle disorder. In both the cases, status epilepticus resolved with anticonvulsive drugs. EPC was successfully treated with levetiracetam, and NCSE with valproic acid. No side effects were observed. Because hyperammonemia and NCSE may have the same features of stupor, a neurophysiological approach might prove useful in differentiating these two conditions. Overall, our results strongly indicate that a correct NCSE diagnosis is mandatory to prevent further deterioration in these patients.

Introduction Metabolic diseases are rare genetic conditions frequently leading to multiorgan involvement. The central nervous system is one of the most frequent targets of these diseases. Developmental delay or mental retardation is common, as well as motor and sensory involvement and epilepsy. First described by Terheggen et al1 in 1969, argininemia (OMIM #207800) is a rare autosomal recessive urea cycle disorder (UCD) (1:2,000,000 live births), caused by the deficiency of the enzyme arginase I, which catalyzes the irreversible hydrolysis of arginine to urea and ornithine. Epilepsy is frequently seen in argininemia ( ►Table 1). In this regard, Terheggen et al2 first described two sisters with spastic paraplegia, epileptic seizures, and severe mental retardation. Furthermore, Vilarinho et al3 reported

received January 17, 2013 accepted after revision August 23, 2013 published online November 20, 2013

argininemia in a 5-year-old child, who, in the absence of spastic diplegia, displayed partial motor seizures over a period of 15 days, which recurred 6 months later. In addition to that, Christmann et al4 described a patient affected by mental retardation and spastic paraparesis first diagnosed with Argininemia at 18 years of age when treatment with valproic acid (VPA) was started for seizures. This patient, who had been hospitalized for repeated generalized seizures responsive to VPA treatment, showed a clinical picture of stupor due to a high concentration of ammonium and arginine (so called VPA sensitivity) which ameliorated after VPA discontinuation. Finally, Carvalho et al5 has recently reported that besides progressive spastic diplegia being the key clinical feature, seizures in argininemia may be more common than previously reported. In their cohort of 16 patients, all but the youngest developed seizures and only 2 of

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DOI http://dx.doi.org/ 10.1055/s-0033-1360479. ISSN 0174-304X.

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Status Epilepticus during the Course of Argininemia

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Table 1 Epilepsy in argininemia: Clinical and neurophysiological data from literature and present article Author/y

No. of cases

Seizures types

EEG

2 cases

Generalized tonic-clonic seizures presenting themselves together with febrile illnesses.

Electroencephalographic dysrhythmia

1 case

Partial motor seizures.

Left temporal and paracentral spikes.

1 case

Generalized tonic seizures.

Generalized and continuous spike-wave discharge at the rate of 3 c/s.

Carvalho et al (2012)5

16 cases

15/16 experienced seizures.

1/16: normal EEG. 14/16: generalized abnormalities. 1/16: focal abnormalities.

Present article

2 cases

Case 1: focal motor seizures/EPC.

Case 1: multifocal spikes.

Case 2: atypical absences.

Case 2: generalized spike-waves.

Terheggen et al (1970)

2

Vilarinho et al (1990)3 Christmann et al (1990)

4

Abbreviations: EEG, electroencephalogram; EPC, epilepsia partialis continua.

16 discontinued the anticonvulsive therapy; the electroencephalogram (EEG) showed generalized abnormalities in all cases but one. Epilepsia partialis continua (EPC) is a rare epileptic manifestation first described by Kozevnikov.6 It represents a special type of focal status epilepticus (SE) defined by Engel as “a combination of focal seizures with continuous twitching in the same area.” EPC is found in Rasmussen Syndrome, focal lesions, and inborn errors of metabolism (IEM). Various conditions affecting energy metabolism, namely Alpers disease or myoclonus epilepsy with ragged-red fibers (MERRF), produce unilateral and then bilateral rhythmic jerks that persist in sleep, with EEG correlates.7 Engel7 classified absence SE (typical and atypical absence SE) as a type of nonconvulsive status epilepticus (NCSE), which occurs both in generalized idiopathic and symptomatic epilepsies. Here we describe two cases of argininemia where either EPC or NCSE were the presenting manifestations of epilepsy.

Methods Clinical, nutritional, biochemical, neurophysiological (digital Video EEG), and magnetic resonance imaging (MRI) data of our patients were collected retrospectively. MRI was performed on a 1.5-T scanner, using T1-weighted and T2-weighted, fluid attenuated inversion recovery, and diffusion-weighted sequences. The study was completed with a single-voxel hydrogen-1 (1H) magnetic resonance spectroscopy (MRS) (TE ¼ 144 ms). MRS was performed with a single circle region of interest (ROI) placed in anterior cingulate cortex.

Case Reports Case Report 1 This boy was first seen at 4 years and 8 months of age. He had developed asymmetrical progressive paraplegia since 2 years of age. Focal motor epileptic seizures occurred at the age of 2 years, when he was started with VPA. Despite the anticonvulsive treatment, at the age of 3 years and 2 months, he experienced a focal secondarily generalized seizure. At that time, a diagnosis of argininemia was made on the basis of Neuropediatrics

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increased plasma arginine (431 μMol/L). Thus, a low protein diet was started in combination with sodium phenylbutyrate 250 mg/kg/d. Repeated EEGs showed focal spikes on the right Rolandic area. At 4 years and 3 months of age, he was hospitalized because he had experienced, during the previous 48 hours, continuous arrhythmic jerks at the left thumb, not impairing his consciousness. The polygraphic-EEG recording (►Table 1 and ►Fig. 1A) showed focal spikes localized on the right rolandic cortex coincident with the muscle potentials on the surface electromyography at the left hand tenar eminence. The electroclinical picture was consistent with the diagnosis of EPC. Plasma ammonia levels were normal and arginine was elevated as usual. EPC was easily stopped over a period of few hours after starting levetiracetam (LEV) 10 þ 10 mg/kg/d IV and then orally. A polygraphic-EEG recording performed 24 hours later showed only focal spikes on the right Rolandic area and the disappearance of the jerks on the left hand thumb (►Table 1 and ►Fig. 1B). No MRI evidence of significant alterations of signal intensity was detectable in the cerebral parenchyma with the exception of a diffuse atrophy with slight ventricular and sulci dilatation. MRS revealed a partial decrease of choline and myoinositol peaks and no significant increase of glutamine peak. The 12-month follow-up EEG showed the persistence of a focal sharp activity localized bilaterally on the motor cortex without clinical signs. VPA was discontinued and currently the patient is only taking LEV 10 þ 10 mg/kg/d orally.

Case Report 2 This patient is a 12-year-and-8-month-old boy from Pakistan. He was diagnosed with argininemia when he was 11 years and 10 months of age because of a metabolic decompensation with hyperammonemia and spastic paraplegia. Thus, he went on a low protein diet associated to sodium phenylbutyrate 250 mg/kg/d. His parents reported that, in the previous 8 months, their child had frequently and suddenly become confused for periods of time lasting approximately 2 to 3 d. During these periods of time, he used to refuse most of the offered food. Repeated blood ammonia measurements were performed and found to be in the upper part of the normal range of our laboratory (from 80 to 95 μg/dL [normal values: 25–94]).

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Fig. 1 Case Report 1. (A) Polygraphic EEG recording showing muscle potentials on surface EMG coincident with focal spikes on right central region of the scalp (epilepsia partialis continua [EPC]). (B) Polygraphic EEG recording after starting levetiracetam showing the disappearance of EPC.

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Fig. 2 Case Report 2. (A) EEG picture during “Stupor” showing diffuse slowing and brief burst of spikes and waves. Normal values of ammonium. (B) Normalized EEG after starting valproic acid. No increase in blood ammonium.

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His EEGs remained normal until the age of 12 years and 8 months when a new one, performed after an episode of stupor (►Table 1 and ►Fig. 2A), showed diffuse slowing of the background activity and frequent short bursts of spike and waves, consistent with NCSE (atypical absences). He was started on VPA 10 mg/kg/d orally and after 24 hours the child became normal and the EEG showed the disappearance of both spikes and waves and diffuse slowing of background activity (►Table 1 and ►Fig. 2B), which was confirmed in his latest follow-up EEG. No increase of ammonium occurred during the administration of VPA. After 48 hours, the VPA was administered orally at the maintenance dosage of 25 mg/kg/d. Within the cerebral parenchyma, no focal lesions with the exception of a mild atrophy with slight ventricular and sulci dilatation were noticed. MRS revealed a partial decrease of choline peak and no significant increase of glutamine peak.

Discussion Both the patients developed epilepsy, and in both cases, SE occurred at a certain time during the course of the disease. Case 1, suffering from focal motor epilepsy, developed EPC in a well-defined area involving only the left upper limb, which was easily stopped with LEV. To the best of our knowledge, this is the first case of EPC described in an UCD. As reported in the literature, a contribution of the primary motor area is indispensable for the generation of EPC.8 Intriguingly, a key symptom of argininemia is progressive lower limbs paraparesis, which is forcibly related to a motor cortex abnormalities. Thus, a hypothesis might be that the involvement of the rolandic cortex in argininemia is responsible for both the progressive paraparesis and the EPC. In case 2, the main manifestation of the epilepsy was a recurring NCSE, which went unnoticed for a long time. VPA,9 together with Ethosuximide and Lamotrigine, is the drug of choice for NCSE, especially for the treatment of typical or atypical absence SE. Although Christmann et al4 reported a VPA-induced hyperammonemia in a patient affected by argininemia, we did not observe hyperammonemia in our patients upon treatment with VPA. On the contrary, patient 2 rapidly ameliorated after VPA and showed no increase of plasma arginine and ammonium over repeated determinations. This could not only be due to the modulation of the metabolic treatment but also demonstrates that, under strict metabolic control, the contraindication for valproate in these cases should not be regarded as absolute. As both NCSE and metabolic decompensation may present with episodes of stupor, and consciousness alteration in these patients is often attributed to hyperammonemia, it is possible that NCSE might be misdiagnosed in argininemia patients with a mild coma and borderline or mildly elevated ammonia levels. This however would be dangerous for the patient in terms of both metabolic balance, considering that SE impairs a normal food intake thereby exposing the patient to the risk of true metabolic decompensation, and quality of life as it impairs all the normal daily life activities and interactions. Therefore, we strongly recommend performing a polygraphic-EEG recording in all the argininemia patients showing episodes of stupor to rule out the possibility of NCSE, mainly in those with slowing of the

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EEG patterns. Polygraphic-EEG recordings may also be useful to demonstrate EPC in patients previously suffering from focal motor seizures. The underlying mechanisms of the neurological involvement in argininemia are still unknown.10 Although ammonia is known to be a neurotoxic compound, in our patients, we could not observe a correlation between hyperammonemia and seizures or SE because they did not occur during metabolic decompensations. High levels of arginine in urine, blood, and cerebrospinal fluid are the biochemical hallmarks of the disease and are not completely normalized by low protein diet and ammonia scavengers. It is possible that chronically high levels of plasma arginine and related guanidine compounds resulting from metabolism of arginine, lead to neurotoxic events, thereby inducing seizures5 or demyelination.10 MRS data showing a decrease of choline and myoinositol peaks do not confirm the findings reported by Carvalho et al11 but are in agreement with previous data in the literature about UCDs.12 Additional MRS investigations are necessary in these patients to understand the relationship between the clinical status and brain metabolites. These two case reports allow to expand the spectrum of the clinical neurological presentation of argininemia involving also focal SE and generalized NCSE besides epilepsy and spastic asymmetrical progressive paraparesis.

Conclusions Epilepsy is more common than previously believed in the phenotype of argininemia. We have described two cases of epilepsy occurring as SE. Recognizing NCSE is advisable in general to allow access to correct therapy thus minimizing its impact on quality of life and development; it is much more mandatory for argininemia patients who are at risk of metabolic decompensation because of fasting while suffering of NCSE. In our patients, epilepsy or SE was easily treated with several anticonvulsive drugs including VPA with no side effects. Thus, these two case reports show that patients with argininemia can be treated with VPA, if it is needed, regardless of the previously described VPA sensitivity,4 providing that they do not undergo fasting, their blood levels of ammonia are frequently controlled and diet and sodium phenylbutyrate treatment are modified accordingly. Furthermore, our cases support the statement made by Carvalho et al5 that SE may be more frequent in argininemia than previously thought. Finally, our findings strongly indicate that underlying metabolic disorders such as argininemia should be taken into account when dealing with EPC or NCSE patients, especially when they present with signs of neurodegeneration.

Acknowledgments R.P. and F.F. gratefully acknowledge “Pierfranco e Luisa Mariani” Foundation (Milan), for the generous funding of their clinical and research activities in metabolic pediatric patients and the secretary of the Center for Metabolic Diseases, Mrs. Vera Marchetti, for her continuous daily help in managing patients’ needs. Neuropediatrics

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Epilepsia partialis continua and generalized nonconvulsive status epilepticus during the course of argininemia: a report on two cases.

Argininemia is a rare inherited disorder of the urea cycle because of a deficiency of the enzyme arginase I causing an increase of arginine and guanid...
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