Hiding in Plain Sight: Functional Neurological Disorders in the News.

OBJECTIVE: Functional movement and seizure disorders are still widely misunderstood and receive little public and academic attention. This is in stark contrast to their high prevalence and levels of associated disability. In an exploratory observational study, the authors examined whether the relative lack of media coverage of functional neurological disorders is in part due to misidentification in "human interest" news stories. METHODS: Thirteen recent news stories from high-impact English-language media outlets that portrayed patients with complex symptoms either attributed to other diagnoses or presented as medical mysteries were identified using online keyword searches. All selected news stories contained video or still images displaying relevant symptoms. Cases were categorized into movement disorders or seizure disorders and were then independently assessed by 10 respective expert raters. For each category, one story of a patient whose symptoms were due to a well-recognized neurological disease was also included. Both the diagnostic category and the respective confidence level were reported by each rater for each case. The interrater agreement was calculated for each group of disorders. RESULTS: The raters confirmed almost unanimously that all presented news stories except the negative control cases portrayed misidentified functional movement or seizure disorders. The interrater agreement and average diagnostic confidence were high. CONCLUSIONS: Functional neurological disorders are often wrongly considered a rare medical curiosity of the past. However, these findings suggest that, while they are largely absent from public discourse, they often appear in the news incognito, hiding in plain sight.

Sleeping in fits and starts: a practical guide to distinguishing nocturnal epilepsy from sleep disorders.

Accurately diagnosing sleep-related events, and particularly distinguishing nocturnal frontal lobe seizures from other sleep disorders such as parasomnias, can be challenging. This article reviews the differential diagnosis of paroxysmal events from sleep, epileptic and non-epileptic, considers important diagnostic points in the history, and evaluates the role of investigations in this setting.

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).

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.

Autoimmune limbic encephalitis.

Autoimmune limbic encephalitis is an increasingly recognised cause of cognitive decline and confusion. The typical presentation is with subacute cognitive decline, behavioural disturbance and seizures. Magnetic resonance imaging may show characteristic changes in the medial temporal regions. The diagnosis is confirmed by identification of elevated voltage-gated potassium channel antibody (VGKC-Ab) titres. It is a highly treatable condition, often responding well to intravenous immunoglobulin or steroids. Recognition of autoimmune limbic encephalitis is sometimes delayed--usually because the diagnosis has not been considered--which can result in long-term neurological consequences.

NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis.

STUDY OBJECTIVES: To describe the semiological features of NREM arousal parasomnias in detail and identify features that can be used to reliably distinguish parasomnias from nocturnal frontal lobe epilepsy (NFLE). DESIGN: Systematic semiologial evaluation of parasomnias and NFLE seizures recorded on video-EEG monitoring. PATIENTS: 120 events (57 parasomnias, 63 NFLE seizures) from 44 subjects (14 males). Interventions. The presence or absence of 68 elemental clinical features was determined in parasomnias and NFLE seizures. Qualitative analysis of behavior patterns and ictal EEG was undertaken. Statistical analysis was undertaken using established techniques. RESULTS: Elemental clinical features strongly favoring parasomnias included: interactive behavior, failure to wake after event, and indistinct offset (all P < 0.001). Cluster analysis confirmed differences in both the frequency and combination of elemental features in parasomnias and NFLE. A diagnostic decision tree generated from these data correctly classified 94% of events. While sleep stage at onset was discriminatory (82% of seizures occurred during stage 1 or 2 sleep, with 100% of parasomnias occurring from stage 3 or 4 sleep), ictal EEG features were less useful. Video analysis of parasomnias identified three principal behavioral patterns: arousal behavior (92% of events); non-agitated motor behavior (72%); distressed emotional behavior (51%). CONCLUSIONS: Our results broadly support the concept of confusion arousals, somnambulism and night terrors as prototypical behavior patterns of NREM parasomnias, but as a hierarchical continuum rather than distinct entities. Our observations provide an evidence base to assist in the clinical diagnosis of NREM parasomnias, and their distinction from NFLE seizures, on semiological grounds.

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.

Epilepsia partialis continua complicated by disseminated tuberculosis and hemophagocytic lymphohistiocytosis: a case report.

BACKGROUND: We describe a patient copresenting with epilepsia partialis continua, tuberculosis, and hemophagocytic lymphohistiocytosis. To our knowledge, this is the first documented case of this triad. CASE PRESENTATION: A 54-year-old black South African woman presented to a hospital in Scotland with an acute history of right-sided facial twitching, breathlessness, and several months of episodic night sweats. Clinical examination revealed pyrexia and continuous, stereotyped, right-sided facial contractions. These worsened with speech and continued through sleep. A clinical diagnosis of epilepsia partialis continua was made, and we provide a video of her seizures. Computed tomographic imaging of the chest and serous fluid analyses were consistent with a diagnosis of disseminated Mycobacterium tuberculosis. An additional diagnosis of hemophagocytic lymphohistiocytosis was made following the identification of pancytopenia and hyperferritinemia in peripheral blood, with hemophagocytosis evident in bone marrow investigation. We provide images of her hematopathology. The patient was extremely unwell and was hospitalized for 6 months, including two admissions to the intensive care unit for ventilatory support. She was treated successfully with high doses of antiepileptic drugs (benzodiazepines, levetiracetam, and phenytoin) and 12 months of oral antituberculosis therapy, and she underwent chemotherapy with 8 weeks of etoposide and dexamethasone for hemophagocytic lymphohistiocytosis, followed by 12 months of cyclosporine and prednisolone. CONCLUSIONS: This combination of pathologies is unusual, and this case report helps educate clinicians on how such a patient may present and be managed. A lack of evidence surrounding the coexpression of this triad may represent absolute rarity, underdiagnosis, or incomplete case ascertainment due to early death caused by untreated tuberculosis or hemophagocytic lymphohistiocytosis. Further research is needed.

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 alpha4, alpha2, or beta2 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.

Familial epilepsy with anterior polymicrogyria as a presentation of COL18A1 mutations.

Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected individuals in the family. Identification of COL18A1 mutations in individuals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.

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.

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.