Nocturnal frontal lobe epilepsy (NFLE) is a rare form of partial epilepsy characterized by bizarre motor behavior that occurs, exclusively or almost exclusively during sleep. It may have varied clinical manifestations including posturing, hypermotor automatisms, and sometimes ambulatory behavior. It can be easily misdiagnosed as nonrapid eye movement (NREM) parasomnias which are paroxysmal behaviors without conscious awareness, that occur during stages 3 and 4 of NREM sleep. NREM arousal parasomnias tend to usually occur during childhood with an episodic pattern, but its onset and persistence during adulthood are rare (1%–11%). Diagnosis of NFLE might be difficult, as interictal and ictal electroencephalogram (EEG) findings are often normal or show nonspecific changes. During the late part of the 20th century, many cases of unusual motor behavior with stereotyped, dystonic, dyskinetic behaviors, without clear-cut ictal and interictal abnormalities in EEG, and with response to anti-epileptic drugs were labeled as "nocturnal paroxysmal dystonia (NPD)." From the first description of this entity, it has been always debated whether it is epileptic or nonepileptic in origin. Later, the term "NFLE" was used to replace "NPD." Studies have shown that both parasomnias and NFLE have a familial pattern. Ictal motor sequence in NFLE may have clear epileptic features (e.g., dystonic posturing and choreiform movements), but they may also be intermixed with parasomnic behaviors such as repetitive rocking, rolling, or ambulation. It can also present as minor motor events such as paroxysmal arousal which may be confused as simple motor parasomnia. Even though certain aspects regarding differentiating parasomnia and NFLE have been discussed previously, it still remains a diagnostic challenge for clinicians.
Restless leg syndrome (RLS) is characterized by unpleasant leg sensations with an irresistible urge to move the limbs (rarely in the upper limb) occurring at night and/or in resting position, improved by locomotion. The leg sensations are commonly described by the patients as crawling, creeping, tingling, pulling, or painful sensations deep inside the legs. It is more commonly seen among females, especially in the elderly age group. It is also associated with uremia, iron deficiency, and pregnancy. It has a circadian pattern with worsening of symptoms in the evening and short remission in the morning after waking up. As the disease progresses, it may also start affecting the upper limbs. Here, we describe a case of NFLE, which presented to us with both symptoms of RLS and NREM parasomnia and posed a diagnosed challenge.
A 56-year-old divorced female who was premorbidly well-adjusted, with medical history of dyslipidemia, hypothyroidism and, diabetes mellitus, with psychiatric history of obsessive–compulsive disorder, was maintaining well on clomipramine 150 mg. She presented to us with 2 years history of insidious onset of symptoms characterized by leg cramps and an irresistible urge to move her lower limbs while she is lying down at night. Patient reported that the urge to move the limbs gets relieved on walking or massaging her legs. The patient had been going through significant psychosocial stressors and reported worsening of symptoms following the death of her mother a year ago. The patient also complained of throbbing headache on and off, with four-five episodes per month which gets relieved on taking analgesics. Neurology consultation was sought, following which magnetic resonance imaging brain, serum iron, serum ferritin, renal function tests, blood counts, liver function tests, and thyroid function tests were done and found to be normal. For symptoms suggestive of RLS, the patient was started initially on clonazepam 2 mg and pregabalin 150 mg. Since there was no relief, she was started on ropinirole 0.5 mg. For the next 3 months, she was lost to follow-up due to financial constraints. On the subsequent follow-up, family members reported that she continued to have RLS-like symptoms, for the evaluation of which she was admitted. She was also noted to have sleepwalking within 15–20 min of sleep onset. Family reported that she had similar episodes of sleepwalking twice in the preceding 2 years, the frequency of which had increased before the admission and started occurring every night. They also reported that she sustained injuries by hitting the wall or furniture while sleepwalking, and it was difficult to wake her up. When the family tried to talk to her during the episodes, her replies were incomprehensible. During the hospital stay, the patient was noted to have a minimum of three-four episodes at night. She was found to have no recollection of these events that occurred during her sleep. She had no past history or family history of either seizure disorder or sleep disorder. No pervasive mood symptoms could be elicited. A sleep study was planned but could not be completed as the patient was unable to lie down for more than a few minutes due to her symptoms during sleep. Video EEG also had to be aborted as she could not stay still. With a high index of suspicion of a diagnosis of NFLE, the patient was started on carbamazepine 400 mg. She showed significant improvement within the 1st day of starting the medication. No further episodes of nocturnal sleepwalking were noted, and unpleasant sensations over the legs had reduced. A 3-h EEG was done while she was on carbamazepine, which showed a mild degree of generalized nonspecific disturbance of electric function. She continued to maintain well on follow-up after a month. Informed consent was obtained from the patient for the write-up of this case report.
NFLE is a form of sleep-related focal epilepsy with heterogeneous presentations involving complex motor behaviors. The focus of seizure is most commonly the frontal lobe; however, it can involve other lobes, accounting for the varied clinical manifestations. The semiology of this case is unique in that it started with RLS-like symptoms and later presented with motor symptoms within 15–20 min of sleep onset. The literature review showed one previous case report of NFLE which presented with RLS-like symptoms. However, there has not been any reported case presenting with both RLS-like symptoms and motor symptoms of sleepwalking.
NFLE and NREM parasomnias can be difficult to distinguish, especially based on history alone. Standing and walking do not, in usual circumstances, help discriminate between NFLE and parasomnias. However, in individuals who can be aroused to full wakefulness after their events, and in whom events have an indistinct offset, standing or walking suggests a diagnosis of parasomnias over NFLE. In addition, stereotypy and dystonic posturing favor a diagnosis of seizures, while features such as yawning, waxing and waning, and prolonged duration (over 2 min) are more common in parasomnias. Techniques such as video EEG may be unhelpful, considering that the restrained environment of video-EEG monitoring restricts elaboration of complex behaviors, especially nocturnal events.
The similarities between NFLE and NREM parasomnias point to a hypothesis of a common underlying pathology which has been explained using MacLean's theory of "triune brain." According to this theory, central pattern generators (CPGs), which are genetically determined motor neural networks embedded in the spinal cord and brain stem of paleomammalian (limbic system) and reptilian brain (basal ganglia) of primates, are controlled by the neomammalian brain (neocortex). Sleep or epilepsy inhibit the neocortex, and facilitated by arousal, lead to the emergence of stereotyped action patterns including oroalimentary automatisms, wandering, and emotional responses (ictal fear). The observation that minor motor events associated with NFLE rarely show a direct association with epileptiform discharges also supports this theory, pointing to the possibility that their genesis is due to nonspecific triggering of CPGs either by epileptiform discharges or fluctuations in arousal.
NFLE can lead to excessive daytime somnolence, which may often be incapacitating and interfere with patient's daily life. Previous studies have shown that about two-thirds of NFLE patients benefit from carbamazepine administration, which in this case lead to the abolition of symptoms. This drug is usually given at low doses (200–1,000 mg at bedtime), abolishing seizures in ~ 20% of cases and giving significant relief (at least 50% seizure reduction) in another 48% of cases. Timely diagnosis and initiation of anti-epileptics can help achieve adequate control of NFLE.
There is a close association between sleep and epilepsy. One of the greatest challenges that clinicians face is in the diagnosis of nocturnal events, particularly in differentiating NFLE from NREM parasomnias. Since eyewitness accounts for nocturnal events are often inadequate, and even techniques such as video EEG may not capture these events, these phenomena are often missed. A careful clinical judgment and a high degree of clinical suspicion are often required for its early diagnosis and treatment.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Bisulli F, Vignatelli L, Provini F, Leta C, Lugaresi E, Tinuper P. Parasomnias and Nocturnal Frontal Lobe Epilepsy
(NFLE): Lights and shadows – Controversial points in the differential diagnosis Sleep Med. 2011;12(Suppl 2):S27–32
2. Derry C. Nocturnal frontal lobe epilepsy
vs. parasomnias Curr Treat Options Neurol. 2012;14:451–63
3. Derry CP, Harvey AS, Walker MC, Duncan JS, Berkovic SF. NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy
: A video EEG analysis Sleep. 2009;32:1637–44
4. Tinuper P, Bisulli F. From nocturnal frontal lobe epilepsy
to sleep-related hypermotor epilepsy: A 35-year diagnostic challenge Seizure. 2017;44:87–92
5. Aricò I, Condurso R, Granata F, Nobili L, Bruni O, Silvestri R. Nocturnal frontal lobe epilepsy
presenting with restless leg syndrome-like symptoms Neurol Sci. 2011;32:313–5
6. Guo S, Huang J, Jiang H, Han C, Li J, Xu X, et al Restless legs syndrome: From pathophysiology to clinical diagnosis and management Front Aging Neurosci. 2017;9:171
7. Zucconi M, Ferini-Strambi L. NREM parasomnias: Arousal disorders and differentiation from nocturnal frontal lobe epilepsy
Clin Neurophysiol. 2000;111(Suppl 2):S129–35
8. Walker MC, Eriksson SH. Epilepsy and sleep disorders Eur Neurol Rev. 2011;6:60
9. Silvestri R, Walters AS. Rhythmic movements in sleep disorders and in epileptic seizures during sleep Sleep Sci Pract. 2020;4:5
10. Nobili L, Proserpio P, Combi R, Provini F, Plazzi G, Bisulli F, et al Nocturnal frontal lobe epilepsy
Curr Neurol Neurosci Rep. 2014;14:424