Inappropriate uncontrollable laughing or crying is common in many neuroscience medicine disorders including after traumatic brain injury or stroke. It can be socially embarrassing and restrict opportunities for social interaction.
This loss of control over emotional responses is known by the term pseudobulbar affect or PBA. Until recently, few therapeutic options were available to treat this condition.
Now a relatively new drug Nuedexta uses a combination of dextromethorphan and quinide to treat pseudobulbar affect. This drug combination has received FDA approval in the U.S.
A recent review article summarized what is known about the pharmacology of the drug dextromethorphan (DM). DM is found in over-the-counter cough medications, for example Robitussin DM.
The DM mechanism of action is felt to be due to the blocking of the NMDA receptor (N-methyl-D-aspartate). This results in a inhibition of the excitotoxic neurotransmitter glutamate. The effect of DM on neurotransmitter function is non-specific and effects on other neurotransmitter systems include:
Inhibition of serotonin reuptake
Inhibition of norepinephrine uptake
Antagonism of the nicotinic acetylcholine receptors
Agonism of sigma1-R gene
Quinidine inhibits CYP2D6 the cytochrome P450 liver enzyme involved in liver enzyme metabolism of DM. This results in much higher and prolonged blood levels of dextromethorphan.
The potential therapeutic targets for DM mentioned in the review include the following:
Pseudobulbar affect
Epilepsy
Pain
Peripheral neuropathy
TBI
Stroke
Alzheimer’s disease (agitation)
I will take a look at some of the specific research studies in these additional targets over the next week or two.
Figure of Advertising Card showing phases of laughter is from Wikipedia Creative Commons. By not known, printed by Young's, The Hatter - eBay store Web page: http://ebay.to/29rwilh Taylor CP, Traynelis SF, Siffert J, Pope LE, & Matsumoto RR (2016). Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacology & therapeutics PMID: 27139517
Currently available antidepressants provide significant relief from major depression in many patients. However, a significant number of patients receive little or limited relief following an initial trial of a standard first-line drug from the selective serotonin re-uptake inhibitor class of agents.
A common clinical strategy after initial drug non-response and non-remission is to consider pharmacological augmentation. Augmentation options for clinicians include lithium carbonate, triiodthyronine (thyroid hormone), a second antidepressant, an atypical antipsychotic or adding psychotherapy if it is not already being provided.
Despite the number and range of augmentation options, additional options need to be explored given the persistence of depressive symptoms in many individuals. A small study from Iran suggests one alternative to consider may be the drug topiramate.
Topiramate is a drug approved by the FDA for the treatment of epilepsy and migraine headaches in the United States. It is not approved for the treatment of any primary psychiatric disorder. The exact mechanism of action for topiramate is unknown although it is known to have effects on the sodium channel, gamma-amino butyric acid (GABA) receptors, glutamate receptors and act as a carbonic anhydrase inhibitor.
Mowla and Kardeh have published a small study of 42 subjects randomized to topiramate or placebo. The key elements of the study include:
Subjects: Adults with DSM-IV major depressive disorder who had failed to respond to eight weeks of treatment with an SSRI drug (fluoxetine, citalopram or sertraline)
Drug: Topiramate 25 mg per day increased by 25 mg per week throughout the trial (mean dosage 175 mg/day) or placebo
Clinical trial design: Double-blind, randomized controlled trial with primary outcome measure the Hamilton Depression Rating scale (HAM-D) administered by a psychologist not involved in treatment
Fifty three subjects started the study with 11 dropouts (six in the topiramate group and five in the placebo group). HAM-D scores statistically decreased more in the topiramate group (21.6 at baseline to 14.7 at 8 weeks) than in the placebo group (21.9 at baseline to 20.8 at 8 weeks).
Since a score of seven or more is considered remission in MDD, the mean score of 14.7 in the topiramate groups suggests significant residual symptomatology. The authors do not provide the number of subjects meeting remission criteria in the topiramate and placebo groups by 8 weeks.
Nevertheless, topiramate has some potential significant advantages in the treatment-resistant major depression population. First, it is a generic drug and would have some cost advantages in comparison to some of the other options. Second, topiramate it typically weight neutral or produces a slight weight reduction. Most antidepressants increase weight over time so this might be an important advantage. Third, topiramate might hold an advantage in treatment of MDD populations with migraine or epilepsy--disorders with an indication for the drug.
This study is too small to change clinical practice patterns or guidelines. Additional larger replication studies need to be considered.
Molecular model of the drug topiramate from Wikipedia Creative Commons file released to the public domain. Author of the model is: Fvansconsellos
Mowla A, & Kardeh E (2011). Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial. Progress in neuro-psychopharmacology & biological psychiatry, 35 (4), 970-3 PMID: 21291943
This work with Challen is heating up and getting more and more interesting every day. I'm away from my beloved Wheeling at the moment, but used one of the simple rules of RBTI today to prevent someone going into a seizure. In fact, the person was so disoriented that she thought she had had a seizure and rushed to the bathroom mirror to look for bite marks on her tongue. But there were no bite marks because the vast majority of seizures are incredibly easy to prevent when you know what Challen refers to as, "The rules of the sugar." In fact, not only was this person's seizure prevented, but ten minutes later the splitting headache was gone, there was no sign of disorientation or loss of coordination, and she was talking 90 miles per hour, smiling, and in a good mood.
And that's just how RBTI is. It's impossibly simple, quick, and easy. So much so that no one believes it.
Anyway, got a good interview coming up on Monday with a person who was bedridden with a side of thyroid cancer six months ago and is in great health today after following the guidance of Challen Waychoff. Thought I would torture all you first with something not pertaining to RBTI...
Here is a month-old interview I did with Armi Legge - a pretty remarkable young triathlete, blogger, and podcaster who is only 16 frickin' years old!!! Way ahead of his time this one. Thanks to Armi for doing it. I owe him and arm and a leg. Haha, ya get it?!!! Bet he hasn't heard that one before.
Epilepsy represents a complex neuropsychiatric condition with significant public health impact. The prevalence estimates of active epilepsy range from about 1 to 4% of the general population. Like other medical conditions, epilepsy appears to increase the risk for a variety of secondary (or cormorbidity problems). Understanding these related risks can aid patients, families and clinicians in understanding symptoms, common presentation conundrums and best treatment approaches. A recent epidemiology survey published by Ottman and colleagues of a large sample of the general population in the U.S. provides insight into the range and relative risk for variety of disorders in those with epilepsy. The key elements of this survey include the following key design items:
Data part of Epilepsy Comorbidity and Health (EPIC) Survey
Mail survey to random households in the United States
Case definition of epilepsy a yes response to the following question: “Have you ever been told you have a seizure disorder or epilepsy?”.
Those who reported being diagnosed with epilepsy (2.0% of those surveyed) were compared to those without a self-reported diagnosis
Surveyed other neuropsychiatric, pain and other medical conditions included: anxiety disorder, depression, bipolar affective disorder, ADHD, sleep disorder/apnea, tremor/movement disorder, migraine, fibromyalgia, chronic pain, neuropathic pain, asthma, diabetes, high blood pressure
Risk ratios controlled for a variety of potential confounding variables including: sex, age, income, population density,census region, prior head injury, and prior stroke
The comorbid conditions with the highest relative risks (that were statistically significant) are shown in the accompanying summary figure. A prevalence ratio of 2.0 would mean those with epilepsy are twice as likely to have the diagnosis compared to controls without epilepsy. ADHD, bipolar disorder, movement disorder/tremor and fibromyalgia led the rank list of diagnoses. A significant number of the disorders showed statistically significant associations between a risk of 1.0 to 2.0. The only disorders that showed no link to a diagnosis of epilepsy were diabetes and high blood pressure.
The primary weaknesses of these types of studies is reliance on self-report diagnosis by a the respondents. One way to exam the validity of diagnoses is to conduct more detailed direct interviews and examinations of a subset of study participants. Also the rates of self-reported diagnoses can be compared to known direct interview studies. Here are the rates of self-reported neuropsychiatric diagnoses in those without epilepsy in the current study: depression 25.6%, anxiety 13.9%, bipolar disorder 6.8%, ADHD 5.5%. The bipolar disorder self-report rates seem unexpectedly high and the implications for the validity of this study is unclear.
The authors note their study demonstrating a lifetime self-report prevalence rate of 2.0% is consistent with previous other population-based surveys. Neuropsychiatric comorbidities were common in those reporting epilepsy ranging from a low of 8.7% for neuropathic pain to 32.5% for depression. The authors note this study will aid those caring for epilepsy and help target comprehensive assessment and managment.
Ottman R, Lipton RB, Ettinger AB, Cramer JA, Reed ML, Morrison A, & Wan GJ (2011). Comorbidities of epilepsy: Results from the Epilepsy Comorbidities and Health (EPIC) Survey. Epilepsia PMID: 21269285
TED presentation by Dr. Aditi Shankardass brings up an important question--should all children with autism (or those undergoing an assessment for autism) have an EEG. The presenter notes that in her experience in India, up to 50% of children referred with a diagnosis of autism have a seizure disorder or some other neurodevelopmental disorder. The TED talk is posted above (7 minutes) and here are my notes from the presentation.
1 in 6 children suffer from developmental disorder
Most diagnosed solely on symptoms
Accuracy of diagnosis improved with laboratory measures
Technology holds hope for diagnosing brain disorder
She worked in a Harvard lab studying mathematical models to measure brain activity
Statistical probability mapping combines EEG and statistical science
She is setting up this technology in India
Case study--seven year old referred with a diagnosis of autism
EEG study was quite helpful
Child did not have autism but had a seizure disorder
Antieplileptic medication resulted in dramatic improvement
She has found a significant number of children diagnosed with autism that had seizure disorders in the Indian referral population, this may be up to 50% of cases
So what about assessment guidelines for autism in the United States and Europe? One of the best autism guidelines I could track down came from the Scottish Intercollegiate Guidelines Network. This free guideline pdf document can be located here. The guideline is titled: "Assessment, diagnosis and clinical interventions for people with autism spectrum disorders. A national clinical guideline".
The guidelines provide a comprehensive review of the evidence supporting a variety of measures in the assessment process. The recommendation from the guideline related to standard EEG assessment is summarized: "Whilst epilepsy is common in children with ASD, there is no indication for an electroencephalogram (EEG) in the absence of other clinical criteria." This recommendation comes with a citation from a 2005 review article by Kagan-Kushnir.
This review notes that seizures occur in 20-30% of children with autism and EEG abnormalities have been found in 10 to 72% of study samples. Subclinical EEG abnormalities have been found in 6-30% of samples. The authors note "There is insufficient evidence to recommend for or against the use of screening EEGs in autistic patients. Given the frequency of seizure disorders in this patient population, a high index of clinical suspicion should be maintained for subtle symptoms of seizures".
The EEG technique referenced by Dr. Shankardassappears to be quantitative EEG or qEEG, a more complex EEG analysis than that done in a clinical setting. qEEG research is ongoing at the TRANSCEND Research laboratory at Harvard directed by Dr. Martha Herbert. Dr. Herbert and colleagues have investigated a variety of EEG research measures in autism. Recent findings indicate that autism subjects show decreased synchrony between the right and left brain hemispheres. The clinical implications of these findings are unclear at this point.
It is unlikely that the percentage of undiagnosed clinically significant seizure disorders in autism in developed countries is high. Nevertheless, clinicians and parents should be alert to potential subtle and non-subtle signs of seizure disorder in those with autism. Additionally, it is not common for a child diagnosed with epilepsy to be misdiagnosed as autistic and to be "cured" by anti-epileptic therapy in the U.S. or Europe. Although not unheard of, this misdiagnosis is reduced with comprehensive multidisciplinary assessments. Concurrent autism and epilepsy (and EEG abnormalities) is a more likely clinical scenario than one disorder being misdiagnosed an the other.
The clinical diagnosis of autism and differential diagnosis of epilepsy continues to be one made primarily by careful history, observation and application of diagnostic criteria. Although this approach is not perfect, it does approach the reliability and validity found for other common medical conditions. When applied in a multidisciplinary setting, this approach is unlikely to misdiagnose a child with epilepsy as having autism alone.
So I think the question of need for an EEG in the context of autism should be left to the discretion of the managing physician. Many will need an EEG as part of the assessment and differential diagnosis. Some may not need them and the the managing physician is best able to make this distinction.
Kagan-Kushnir T, Roberts SW, & Snead OC 3rd (2005). Screening electroencephalograms in autism spectrum disorders: evidence-based guideline. Journal of child neurology, 20 (3), 197-206 PMID: 15832609
Isler JR, Martien KM, Grieve PG, Stark RI, & Herbert MR (2010). Reduced functional connectivity in visual evoked potentials in children with autism spectrum disorder. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology PMID: 20605520
