Misdiagnosis of menstruation-related recurrent hypersomnia as epilepsy in a patient with generalized epileptic discharges.

Recurrent hypersomnias are very rare with two subtypes as Kleine-Levin syndrome and menstruation-related hypersomnia, which is very rarely encountered worldwide. Here, we report a young girl with menstruation-related recurrent hypersomnia, who was misdiagnosed as epilepsy due to co-existing generalized epileptic discharges. The importance of this comorbidity in terms of differential diagnosis of the attacks is discussed.

Introduction

The term “recurrent hypersomnia” was first described by Kleine in 1925.[1] According to International Classification of Sleep Disorders, they are classified under the title of central hypersomnias.[2] According to these criteria, at least one hypersomnia attack lasting between 2 days and 4 weeks should be observed in 1-year; alertness, cognitive functions, and behaviors should be normal between attacks. Recurrent hypersomnias are very rare with an incidence of approximately 2.5 in 10,000,00.[34] It has two subtypes as Kleine–Levin syndrome and menstruation-related hypersomnia, which is very rarely encountered worldwide.[345] Here, we report a young girl with menstruation-related recurrent hypersomnia, who was misdiagnosed as epilepsy due to co-existing generalized epileptic discharges.

Case Report

A 14-year-old girl was brought to our epilepsy department. Her first attack was noticed 6 months ago when her mother went to her bed to awaken her. She could not gain her full consciousness with blurred speech. When she was forced to stand up, parents noticed that she was not able to walk without support. She was taken to a state hospital and internalized for 3 days in intensive care unit. Biochemical tests, cranial magnetic resonance imaging, and lumbar puncture analysis were normal. Electroencephalography (EEG) showed random generalized epileptic discharges with the photic sensitivity. She was diagnosed to have idiopathic generalized epilepsy and given valproic acid (750 mg/day). She had no history of convulsions. The attack lasted for about 4 days. No changes of personality, appetite or sexual behavior were noticed by the family. No triggering factor was noticed by the parents. At the end of about 1-week, the patient was in premorbid condition without any residual symptoms.

The second attack occurred 4 months later, characterized same as the previous attack, but lasted for 5 days. She had a tendency to sleep, difficult to be awakened and had decreased responses to external stimuli, including pain. This attack was also decided to be of epileptic in origin; the dose of valproic acid was increased to 1250 mg/day, and antibiotics were given for infection of undetermined etiology suggested by increased serum inflammatory markers. This second attack lasted for about 4 days, similar to the previous one, without any accompanying change in personality, appetite or sexual behavior.

Four months after this event, she had another attack and was brought to our department. She was still within attack period, which had started 3 days ago. We performed continuous video-EEG monitoring, and it revealed that the patient was in sleep [Figure 1]. The latest attack lasted for 5 days, with full recovery of the child without any neurological symptoms. Repeated EEGs demonstrated randomly occurring generalized epileptic discharges with the photic sensitivity [Figure 2], irrespective of the clinical status of the patient. A detailed medical history revealed that she was at menarche with irregular menstruations, coinciding with the attacks. Of three attacks, two started 2 days before menstruation, and the last attack started simultaneously with the menstruation. There were no associated features of behavioral or cognitive abnormalities, compulsive eating, sexual disinhibition or delusions/hallucination. The patient, however, was confused during the attacks with some degree of feeling of unreality. There was no sign of dysautonomic features or psychiatric comorbidity. Family history revealed that her father had primary generalized epilepsy that was cured for more than 10 years.

Figure 1

Continuous video-electroencephalography monitoring during her third attack showing that the patient was asleep

Figure 2

Repeated electroencephalography demonstrated randomly occurring generalized epileptic discharges with the photic sensitivity after her last attack ceased

The patient was diagnosed as menstruation-related recurrent hypersomnia. Co-existing generalized epileptic activity was accepted as an incidental comorbidity, and because there was no history of seizures (generalized tonic-clonic, absence, myoclonic, or any other), the patient was not diagnosed as having epilepsy. She was given carbamazepine with a daily dose of 400 mg. At the end of 19 months follow-up duration, she is still symptom-free.

Discussion

Menstruation-related recurrent hypersomnia is a very rare clinical entity. It is not yet clear whether this disorder is a variant of Kleine–Levin syndrome or a separate entity.[46] This syndrome is characterized by recurrent episodes of hypersomnia, with or without other symptoms of Kleine–Levin syndrome, but associated with menstruation and/or puerperium.[7] The classical features of Kleine–Levin syndrome as changes in mood, behavior or appetite were not present in our patient. Other than menstruation, an additional trigger such as infections of first exposure to alcohol may also accompany sleep attacks in menstruation-related recurrent hypersomnia.[35] In our patient, the second attack was precipitated by menstruation and an infection of undetermined origin while other attacks were not associated with any precipitating factors other than menstruation.

Diagnosis of Kleine–Levin syndrome can be very difficult as there is no single symptom that can positively make the diagnosis, but a long list of investigations are needed to eliminate other conditions that mimic its symptoms or cause symptomatic Kleine–Levin syndrome.[5] Although uncommon, secondary causes of hypersomnia were previously reported such as head trauma, brain tumors, stroke or other structural abnormalities affecting hypothalamus, frontal and/or temporal lobes, hippocampus, uncus and amygdaloid body.[3] In primary cases of hypersomnia, on the other hand, neuroimaging investigations should be normal or almost normal.[8] In the presented case, the association of menstruation-related recurrent hypersomnia and generalized epileptic discharges were accepted as a genetic trait, and no causal relationship could be suggested. On the other hand, the importance of this comorbidity in terms of differential diagnosis of the attacks should be underlined. Nonconvulsive status epilepticus and absence status should also be differentiated in such cases, which were excluded in our patient with video-EEG monitoring. Nevertheless, a detailed medical history and careful electrophysiological investigations during the attacks are of crucial importance in order for an accurate diagnosis of this rare disorder and appropriate treatment.

Prophylactic treatment of menstruation-related recurrent hypersomnia includes oral contraceptives.[6] Other agents used in prophylactic treatment of Kleine–Levin syndrome, such as lithium, carbamazepine or valproic acid, may be used with variable degree of benefit. The effect of carbamazepine is unknown; interaction with adenosine-binding sites in the brain rather than inhibition of sodium channel activity may be suggested. Treatment with stimulant medications during the attacks could also be effective. These treatment options were discussed with the family and a prophylactic treatment with carbamazepine was chosen due to possible side effects of oral contraceptives, lithium, and valproic acid. Also, she had had recurrent attacks under treatment with valproic acid given for misdiagnosis of epilepsy. Under carbamazepine treatment, there was no recurrence of hypersomnia or need for stimulant medication. The patient is still followed-up in our out-patient clinic without any symptoms.