Cannabadiol For Epilepsy

Cannabadiol, an extract of marijuana different from the THC ingredient in which most forms of hemp used as a recreational drug are enriched, has been in clinical trials for several years. This is the first good quality, large trial of the drug in the US to be published.

Note that most persons purchasing hemp oil for its CBD content are using between 1/100th and 1/10th the dosage used in this study (20 mg/kg would be 1400 mg in a 70 kg adult, and see, for example, online published dosages for CBD oil here). So most "medicinal" users of marijuana who are using the medication for seizure prevention are not likely to be getting a therapeutic dosage of CBD in their herbal intake.

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ABSTRACT

Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome

Orrin Devinsky, M.D., J. Helen Cross, Ph.D., F.R.C.P.C.H., Linda Laux, M.D., Eric Marsh, M.D., Ian Miller, M.D., Rima Nabbout, M.D., Ingrid E. Scheffer, M.B., B.S., Ph.D., Elizabeth A. Thiele, M.D., Ph.D., and Stephen Wright, M.D., for the Cannabidiol in Dravet Syndrome Study Group*

N Engl J Med 2017; 376:2011-20

20 May 25, 2017

DOI: 10.1056/NEJMoa1611618

BACKGROUND

The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.

METHODS

In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.

RESULTS

The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.

CONCLUSIONS

Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)

Some close up observations regarding the 2017 Hawaii rat lungworm problem.

Courtesy Wikipedia photo

Blogger grand rounds, and the rest of a story.

Early this April, last month, a youngish adult male, of Tongan birth, presented to the local emergency room with diffuse head, extremity, and body pain, fever, and poor appetite. He denied nausea. He had fever, cough, and diffuse myalgias, with temperature 38 C (minimal fever) and blood WBC elevated at 21.7/nL with 83% neutrophils, 5% bands,3% eosinophils. Chest X-ray was clear. He was discharged with doxycycline and hydrocodone prescriptions.

He returned a day later, with cough and dyspnea. WBC was down to 15.9/nL, with 1% bands and 6.7% eosinophils; he was discharged with an inhaler for bronchitis.

He returned to ER again 5 days later, with resolution of the body aches, cough and dyspnea but a 3 1/2 day history of bilateral dull headache and constant, sharp pain in the left chest, leg and lateral foot. He was afebrile. WBC was 28.4/nL with 18% bands and 4% eosinophils. LP showed 160 WBC/microL with 92% lymphocytes, 3% monos, 3% neutrophils, 2% eosinophils, protein elevated at 105 mg/dL, glucose normal. He was given antibiotics, antivirals, and hydration. The current writer was consulted, and it was felt the patient either had HSV-2 or early angiostrongylus meningitis with radiculitis. When questioned about exposures, the patient denied consumption of unwashed produce. He depends on catchment of rain for wash water, but drinks only bottled water. DNA PCR for HSV-2 had been negative, and an addtional request done at that time for angiostrongylus cantonesis DNA was also negative. Dexamethasone and albednazole was added, and patient felt well enough to be discharged the next day, after having received 400 mg of albednazole and 8 mg of dexamethasone total since the day before.

However, the global headache and left leg and foot pain remained, and the patient was unable to pay for the remaining doses of albednazole as an outpatient. He returned to the hospital four days later and was given analgesics and additional dexamethsone. Eleven days after that, he returned to the ER with continued headache and left leg and foot pain, and a second LP showed 650 WBC/microL with 80 lymphs, 11% eosinophils, 5% neutrophils, and 4% monos. CSF protein was 120 with normal glucose.

Additional history was obtained. Spoiler alert! :-) Note that anyone who can figure out a particular identity from the above lab values has already got the medical records. No HIPAA issues here.


In late March, about a week prior to onset of symptoms, the patient had consumed kava with 5 other men. The kava had been stored outdoors in an open container, and was later found to have been contaminated, with a slug found at the bottom of the kava bowl after the kava beverage had already been consumed.

Two of those men found out about the patient's diagnosis and presented to the Hilo Medical Center's emergency department just one day following the patient's hospital discharge (the day after I had first spoken to him). These men were friends and confidants of the patient who were aware of the patient's illness. They were evaluated in the ER with LP and had were diagnosed with eosinophilic meningitis, with CSF samples showing typical high WBC with eosinophlia and high protein with normal glucose. History given by two of these men, interviewed the day after the initial index patient's subsequent second LP, indicated that in the weeks following the contaminated kava ingestion all 6 of the men had become ill with symptoms including headache. Yet, only those later two were initially diagnosed with typical CSF findings on initial LP, and our patient, who was actually the first of the six to have a spinal tap, had negative CSF PCR testing for Angiostrongylus DNA on his first LP, and was only considered a probable case until the second LP. The other three contaminated kava partakers have not to my knowledge yet been confirmed to have had eosinophilic meningitis, even though they were symptomatic from their exposure to the organism.

Dateblood WBC (per nanoliter)blood % eosCSF WBC (per microliter)CSF % EOS
Initial presentation (pre-meningoradiculitis)29.42
One week later, 4 days post meningitis onset24.810 1602
3 weeks later24.40 650 11

Consider the type of parasitic infection that is due to Angiostrongylus cantonesis. This tiny nematode roundworm spends its adult stage in the pulmonary arteries of the rat, within the rat's lungs, whence the common name "rat lungworm." The adult worm drops its eggs, which hatch into first stage larvae (about 0.27 to 0.30 mm length) which travel downstream in the lungs, rupture the alveoli, and travel with associated lung fluids up to the trachea and rat throat, where they are swallowed and pass out with feces to the ground. There, the first stage larvae may be ingested by molluscs such as snails and slugs. Once in the snail or slug, the first stage larvae live in the body of the mollusc for at least 45 days during which they mature through their first and second (0.42 to 0.47 mm length) molts to reach the third larval stage (0.42 - 0.49 mm length), where they are capable of infecting vetebrates, such as rats, which might eat the slugs. In addition, if the slug dies, the larvae may move out of the slug's body and live up to several days. Potentially infective larvae have been detected in slime trails of infected Australian snails, suggesting that contacts other than actual slug ingestion may allow infection to occur.

Once the vertebrate host ingests the third stage larvae, they enter the gut, then exit the intestine via tunneling into the veins. Entering the circulation, they are carried throughout the body, with large numbers lodging in the terminal circulation of the brain and spinal cord. From there, the third stage larvae move to the meninges, where they produce eosinophilic meningitis while maturing to the fourth and final larval stage (0.85-1.0 mm length) within about a week. The fourth stage larvae migrate within the central nervous system for about 12 days in rats and then molt into the adult worms which, in the rat, re-enter the venous circulation and are carried to the pulmonary arteries, where they fully mature (15.5-23.0 mm length and 0.25-0.35 mm diameter) and the life cycle then repeats.

Rats seem required for the nematode to reach its adult form and complete its life cycle. When the parasite is accidentally ingested by humans or monkeys, the fourth stage larvae do not generally reach adulthood or leave the central nervous system, instead dying in place while causing meningitis, often with radiculitis and occasionally also encephalitis, in the brain and spinal cord regions where they have migrated.

Comments from the front lines:

  • 1. Eosinophilic meningitis is a rare illness in this country and state, even on the Big Island. I have seen only a couple dozen cases in the past 7 years, and yet I think that has given me more experience with the acute presentation of the illness than any other neurologist whose practice has been confined to US soil. Neurologists in certain other countries, like Thailand, have far more experience with this disease.
  • 2. Secondary contamination of food and drink, consumed by a group, provides us with a natural experiment in the complex relationships between exposure to an infectious agent and disease and between disease and public health statistics.
    It seems to us who count hospitalizations for eosinophilic meningitis that there are two to three times as many cases of rat lungworm disease as the state health department is willing to release as numbers to the media, because the State's current criteria for diagnosis requires CSF to be positive for DNA by PCR, which seems, from my perspective, to not be a completely sensitive test, missing perhaps 50% of early cases.
    I am certain that milder cases are commonly not diagnosed, because an LP is generally not done in milder cases. Consider the six symptomatic men who drank the slug-contaminated kava, all of whom, I was told, became ill. How many officially documented cases has the health department counted of the 6? Perhaps 3? I am understanding of the need to not overdiagnose this rare condition, but I wonder if the fact that the two biggest economic drivers of the Big Island economy -- tourism and agriculture -- may be at risk if the problem increases might influence the State to minimize its morbidity count?
  • 3. Albednazole-dexamethasone combination therapy is probably better than the CDC recommendation of prednisolone therapy alone. Personal experience here: when I first started seeing acute cases of the illness, in early 2011, I used prednisone alone, as per the official federal government CDC in Atlanta's recommendation, and I saw a couple cases get worse over weeks. I since have given albednazole, currently for 1 week with dexamathasone for 1 week, and have not seen any more of that subacute worsening. I believe that albednazole prevents maturation and further migration of the parasites if given early.
  • 4. The current United States pricing on albednazole is obscenely high. How high is that? Online, getting imported mail-order 90 tabs of generic albednazole 400 mg is about $80. The US pharmacy price is for the same amount is over $40000.
    This huge price discrepancy is due both to US restrictions on drug imports and regulations making it harder for generic chemical factories to make FDA approved generics. The Obamacare Act failed to fix this known problem with affordability, despite the name of the Act. Thanks Obama. I don't really fault the drug companies for being predators. They are what they are. I fault the US for failing to allow free markets, thus allowing those monopolies protected access to their continued sucking of US health consumer money.
  • 5.Published accounts of Angiostrongylus cantonesis meningitis infections suggest a prodrome of abdominal pain or nausea prior to the meningitis, but in this and many other cases the prodrome suggests a systemic immune response with a type I hypersensitivity component.
    The flulike symptoms and a cough treated with bronchodilators in the case above (and many others in my experience) might be that of the body reacting systemically to the presence of the parasite in the circulation before the meningitis itself begins. This is where a screening blood test, perhaps for some kind of antigen, might be possible and allow early diagnosis. At present there is no such test.
  • 6. There is a category of chronic pain and fatigue patient who tends to decide that their symptoms are evidence that they suffer from an undiagnosed case of the chronic infection dejour, be it yeast, Lyme, or, here in Hawaii, rat lungworm.
    For further perspective here, just ask any infectious disease specialist in the Northeast about chronic Lyme. When I say above that in my experience that eosinophilic meningitis on the Big Island is under-diagnosed, I should emphasize I mean acute cases are under-diagnosed, not any chronic illness.

Cannabadiol For Epilepsy

Cannabadiol, an extract of marijuana different from the THC ingredient in which most forms of hemp used as a recreational drug are enriche...