Christopher P. Derry

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment.

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

Paroxysmal Motor Disorders of Sleep: The Clinical Spectrum and Differentiation from Epilepsy

Summary:  The diagnosis of paroxysmal events in sleep represents a significant challenge for the clinician, with the distinction of nocturnal epilepsy from nonepileptic sleep disorders often the primary concern. Diagnostic error or uncertainty is not uncommon in this situation, particularly with respect to nocturnal frontal lobe epilepsy (NFLE), which has a variable and often unusual presentation. Such errors can be minimized if the range of nonepileptic disorders with motor activity in sleep is fully appreciated. Here we review these disorders, before discussing the important clinical and electrographic features that allow their accurate differentiation from seizures. Particular emphasis is placed on the differentiation of nocturnal frontal lobe epilepsy from non–rapid eye movement (NREM) arousal disorders and other parasomnias. The value of recording episodes with video EEG polysomnography is discussed.

Epilepsy and mental retardation limited to females: an under-recognized disorder

Epilepsy and Mental Retardation limited to Females (EFMR) which links to Xq22 has been reported in only one family. We aimed to determine if there was a distinctive phenotype that would enhance recognition of this disorder. We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were transmitted through carrier males. Detailed clinical assessment was performed on 58 individuals, using a validated seizure questionnaire, neurological examination and review of EEG and imaging studies. Gene localization was examined using Xq22 microsatellite markers. Twenty-seven affected females had a mean seizure onset of 14 months (range 6-36) typically presenting with convulsions. All had convulsive attacks at some stage, associated with fever in 17 out of 27 (63%). Multiple seizure types occurred including tonic-clonic (26), tonic (4), partial (11), absence (5), atonic (3) and myoclonic (4). Seizures ceased at mean 12 years. Developmental progress varied from normal (7), to always delayed (4) to normal followed by regression (12). Intellect ranged from normal to severe intellectual disability (ID), with 67% of females having ID or being of borderline intellect. Autistic (6), obsessive (9) and aggressive (7) features were prominent. EEGs showed generalized and focal epileptiform abnormalities. Five obligate male carriers had obsessional tendencies. Linkage to Xq22 was confirmed (maximum lod 3.5 at = 0). We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with convulsions in infancy, often associated with intellectual impairment and autistic features. The unique inheritance pattern with transmission by males is perplexing. Clinical recognition is straightforward in multiplex families due to the unique inheritance pattern; however, this disorder should be considered in smaller families where females alone have seizures beginning in infancy, particularly in the setting of developmental delay. In single cases, diagnosis will depend on identification of the molecular basis.

Sleep and epilepsy

The intimate relationship between sleep and epilepsy has long been recognized, yet our understanding of the relationship is incomplete. In this article we address four key issues in this area. First, we consider the reciprocal interaction between sleep and epilepsy. Sleep state clearly influences seizure onset, particularly in certain epilepsy syndromes. The converse is also true; epilepsy may disrupt sleep, either directly through seizures and epileptiform activity, or indirectly through medication-related effects. Unraveling the influences of sleep stage, epilepsy syndrome, and drug effects is challenging, and the current state of knowledge is reviewed. Secondly, accurate diagnosis of sleep-related epilepsy can be difficult, particularly the distinction of nocturnal frontal lobe epilepsy (NFLE) from arousal parasomnias. The challenges in this area, along with work from the authors, are discussed. Thirdly, we will explore the putative relationship between obstructive sleep apnea (OSA) and epilepsy, including the effect of OSA on quality of life; this will lead us to a brief exploration of the effects of OSA on neuroendocrine function. Finally, we will review the evidence surrounding the role of sleep in sudden unexpected death in epilepsy (SUDEP).

Increased serotonin receptor availability in human sleep: Evidence from an [18F]MPPF PET study in narcolepsy

Data from animal studies suggest that serotonin release promotes wakefulness and suppresses REM sleep, but there are dangers in extrapolating these findings to humans. Binding of the radioligand [18F]MPPF to 5HT1A receptors is sensitive to levels of endogenous serotonin. In this study, we aimed to demonstrate changes in serotonin receptor availability in the human brain in wakefulness and sleep using [18F]MPPF and positron emission tomography. 14 subjects with narcolepsy cataplexy underwent [18F]MPPF PET scans in wakefulness and in sleep. Subjects who used the stimulant methylphenidate took their normal medication for the wake scan but omitted it prior to the sleep scan. The change in binding potential (BP) between the sleep and wake scans was examined using paired t test. Methylphenidate is thought to have little or no effect on serotonergic neurotransmission, and in order to confirm the absence of an effect on [18F]MPPF binding, a concurrent study was performed using a beta-microprobe technique to examine the effect of methylphenidate administration on [18F]MPPF binding in Sprague-Dawley rats. The human study showed a significant increase in [18F]MPPF binding in sleep compared to wakefulness in the whole brain and all regions of interest examined (temporal cortex, mesial temporal region and cingulate cortex). The beta-microprobe study confirmed that methylphenidate administration had no effect on [18F]MPPF binding. These findings indicate that serotonin receptor availability is increased in sleep compared to wakefulness in narcoleptic humans.

Medication management in people with Parkinson's disease during surgical admissions.

Background Patients with Parkinsons disease (PD) may experience problems in hospital, with their medication being withheld or inappropriate medication being prescribed. Since surgical admissions present particular risks, the authors examined the management of patients with PD on surgical wards. Methods All patients with PD admitted to surgical departments in Aberdeen Royal Infirmary during an 18-month period were identified. Medical and nursing notes were reviewed retrospectively, and drug prescription and administration were studied in detail. All documented complications were recorded. Results 59 surgical admissions (51 receiving PD medication, median duration 6 days) were studied. 71% had missed doses of PD medication, with 34% missing over 10% of prescribed doses. Values were similar for levodopa and agonists. Overall, 12% of all prescribed PD medication was missed (mean 0.7 missed doses per patient per day). No reason for missed doses was recorded in 64% of cases, while inappropriate reasons included ‘out of stock’ (12%) and ‘nil by mouth’ (8%). Centrally acting antidopaminergic drugs (mainly antiemetics) were prescribed in 41% of cases, and administered in 22%. Complications, most commonly neuropsychiatric, were documented in 69% of non-day-case admissions. Conclusion Poor prescribing and incomplete drug administration are common in patients with PD on surgical wards. Measures to improve management are identified.

Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a relatively benign epilepsy syndrome with few comorbidities. Here we describe two families with unusually severe ADNFLE, with associated psychiatric, behavioral, and cognitive features. Detailed clinical data on 17 affected individuals were obtained, and genotyping of microsatellite markers, linkage analysis, and sequencing of candidate genes was performed. The severe ADNFLE phenotype in these families was often refractory to treatment, with status epilepticus occurring in 24% of subjects. Psychiatric or behavioral disorders occurred in 53%, with intellectual disability in 24%, and developmental regression in two individuals. No mutations were identified in α4, α2, or β2 nAChR subunits. In one family there was evidence of linkage to a region of 15q24 without nAChR subunit genes. In conclusion, severe ADNFLE has significant medical, psychiatric, and intellectual morbidity. The molecular basis of severe ADNFLE is unknown but may involve non‐nAChR‐related mechanisms.

Unihemispheric cerebral vasculitis mimicking Rasmussen’s encephalitis

A previously healthy 10-year-old boy presented with right-sided headache and focal motor seizures characterized by left facial twitching. Examination revealed a left hemiparesis. CT scan demonstrated a large, right frontoparietal mass containing calcification. Biopsy showed changes consistent with cerebral vasculitis involving the cortex, white matter, and leptomeningeal vessels. Despite treatment with dexamethasone 3 mg/day for 6 weeks, the patient’s condition deteriorated, with increasing left-sided weakness and a new left hemianopia. On re-investigation, inflammatory markers, autoantibody profile, and neurotropic virus screen were negative. CSF examination revealed intrathecal synthesis of oligoclonal bands but was otherwise normal. A cerebral angiogram showed the right middle cerebral artery and its branches to be of smaller caliber than the left. In view of the re-activation of the cerebral vasculitis, treatment with 2 mg/kg/day prednisolone was given for 3 months. His condition stabilized, and azathioprine was introduced as a steroid-sparing immunosuppressive therapy. Despite occasional focal seizures, he remained stable for the next decade, at which time the azathioprine therapy was withdrawn. Serial MRI was …

The sleep manifestations of frontal lobe epilepsy.

Frontal lobe seizures have a tendency to occur from sleep, and in some cases occur exclusively (or almost exclusively) from sleep; these individuals are said to have nocturnal frontal lobe epilepsy (NFLE). NFLE can be difficult to distinguish clinically from various other sleep disorders, particularly parasomnias, which also present with paroxysmal motor activity in sleep. Here, the manifestations of frontal lobe epilepsy are reviewed in detail, with particular reference to the influence of sleep and the characteristics of NFLE. Key aspects of differential diagnosis are also considered, and the underlying mechanisms involved in NFLE discussed.

Nocturnal Frontal Lobe Epilepsy vs Parasomnias.

Opinion statementThe diagnosis and treatment of nocturnal events can present significant challenges to the clinician. Correct diagnosis is the first step towards appropriate treatment, but may not be straightforward. In particular, non-rapid eye movement (NREM) arousal parasomnias, such as sleepwalking, sleep terrors, and confusional arousal can present in a similar fashion to nocturnal frontal lobe epilepsy (NFLE); dramatic and often bizarre behaviors from sleep are features of both conditions, and may result in diagnostic confusion. A careful clinical history, however, often enables accurate diagnosis, and the frontal lobe epilepsy and parasomnia (FLEP) scale, a validated questionnaire for the diagnosis of nocturnal events, can add diagnostic confidence. Recording of events on video-EEG-polysomnography is required if diagnostic doubt remains although is not always achievable, particularly if events are occurring infrequently. Treatments for NFLE and parasomnias are different, but lifestyle modification and treatment of coexisting sleep disorders (such as obstructive sleep apnoea) may have a role in both. In NFLE, medical treatment with antiepileptic drugs, particularly carbamazepine and topiramate, forms the mainstay of treatment; a small proportion of individuals with treatment-resistant seizures may benefit from epilepsy surgery. For parasomnias, reassurance and the removal of priming and precipitating factors is often sufficient. A minority of individuals will, however, need medical treatment, usually with benzodiazepines or tricyclic antidepressants. Unfortunately, there are few data on which to base treatment decisions in this area, with the evidence comprising predominantly case reports and case series. Well-designed studies, including randomised control trials, are needed and may require a multicentre approach.