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Canna~Fangled Abstracts

Medical Cannabis as an Effective Treatment for Refractory Symptoms of Paraneoplastic Stiff Person Syndrome

By November 20, 2019July 10th, 2024No Comments

Diane Portman, MD∗'Correspondence information about the author MD Diane Portman, Kristine A. Donovan, PhD, Margarita Bobonis, MD Department of Supportive Care Medicine, Moffitt Cancer Center, Tampa, Florida, USA

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DOI: https://doi.org/10.1016/j.jpainsymman.2019.11.007

To the Editor

Stiff person syndrome (SPS) is a disorder characterized by fluctuating, progressive, and painful spasms of the limbs, trunk, and face. The condition is frequently associated with other diseases, including malignancies.

Up to 10% of SPS cases are paraneoplastic (PSPS) and occur with various types of cancer.
SPS is thought to be immune-mediated, with up to 60% of patients demonstrating antibodies to glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the production of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Central nervous system (CNS) disinhibition is deemed the likely cause of increased muscular activity. Investigations of PSPS have also shown autoantibodies directed against amphiphysin, an endocytosis-associated immunogenic neural protein expressed in cancer cells.
Imaging may be negative and electromyography may be normal or demonstrate continuous spontaneous discharges. Treatment of SPS with immunotherapy and drugs that increase GABAergic tone may reduce spasms and stiffness. Anticancer treatments may mitigate PSPS. However, outcomes are unpredictable and remissions are uncommon.
GABAergic dysfunction in SPS may also engender psychiatric comorbidities. Emotional stress and sudden auditory, visual, or tactile stimuli often trigger or flare symptoms. Owing to unexpected startle responses, patients may demonstrate anticipatory anxiety and task-specific phobias. Physical limitations, social isolation, pain, and psychiatric disturbances are associated with reports of poor quality of life.
Because of the variable response to treatments, patients may use alternative products to manage PSPS symptoms that federally licensed pharmaceuticals may only partially control. As cannabis derivatives have been associated with reduction of spasticity, muscle spasm, and neuropathic pain, a number of U.S. state medical marijuana programs have authorized non–FDA-approved cannabinoids for conditions with such symptoms, for example, multiple sclerosis.
Although one case report described beneficial effects of a licensed cannabis derivative [tetrahydrocannabinol (THC)/cannabidiol (CBD)] oromucosal spray (Sativex®) for non–cancer-related SPS outside the U.S.,
there is no literature about use of state-authorized medical cannabis products for SPS or any cannabinoid for PSPS.
Our case highlights significant reduction of refractory PSPS symptoms with use of medical marijuana.

Case Description

A 60-year-old woman presented with repetitive and prolonged episodes of painful facial spasms and trismus.
The patient was diagnosed with metastatic breast cancer in 2010 after lumpectomy and lymph node dissection with pathology of invasive ductal carcinoma. She refused conventional treatment and pursued alternative approaches. The patient reported chronic right-sided back pain, sciatica, and “dystonic contractions” of the back muscles secondary to a 1982 motor vehicle accident and was treated with paraspinal botulinum toxin injections, opioids, and gabapentin.
In 2011, she developed bone metastases and pathologic fracture of the C2 vertebral body. Owing to disease progression, she underwent a succession of systemic and locally directed anticancer therapies.
In 11/17, the patient reported nighttime “limb jerking” deemed likely hypnogogic movements. In 4/18, she reported worsened “twitching,” causing her to drop items. The twitches were thought to be related to gabapentin, which was discontinued.
In 5/19, the patient developed multiple and prolonged debilitating painful facial spasms, with no alteration in consciousness. Facial contortions were marked, with severe jaw clenching that resulted in broken teeth. Neuro-oncology evaluation included CT head, MRI brain and total spine, EEG, and CSF fluid analysis. Imaging studies were negative, and EEG revealed no seizure. CSF fluid analysis revealed nonspecific elevation of IgG and cytology was negative for malignancy. The initial paraneoplastic autoantibody panel was negative.
Her presentation was deemed consistent with PSPS, and treatments were provided by supportive/palliative care and neuro-oncology for symptom control and immune-modulation. She was started on IVIG with no improvement. Initial medications for spasms and anxiety included baclofen and benzodiazepines, with minor response to lorazepam when taken at the onset of facial spasms. However, sedation limited dosing. She found increased comfort with application of an ice mask to the face and use of oxycodone for pain. Gabapentin was resumed and exerted minimal effect despite escalations.
Repeat anti-GAD antibody was positive (69 IU/mL). She received rituximab in 5/19. Thereafter, she reported frequent dissemination of spasms affecting the arms and back muscles. Restaging showed progression of breast cancer metastases and new chemotherapy was initiated in 7/19.
She received plasma exchanges, with unchanged frequency, but subjectively decreased intensity of spasms. The anti-GAD antibody decreased to <5 IU/mL three-week post-plasma exchange. She subsequently developed whole-body spasms with dystonic posturing of the hands and feet. After evaluation in the neuromuscular/movement disorder clinic, botulinum toxin injections were advised for dystonia. These were deferred owing to concern for risks of administration in the setting of startle responses that exacerbated contortions. Electromyography was reported as normal. The muscle relaxant metaxalone was added with transient decrease in spasms.
The patient reported new onset of depressed mood and became reluctant to leave her home. A family member urged intervention, and the patient was referred to a supportive/palliative care team psychiatrist.
At the time of the 9/19 supportive/palliative care and psychiatry assessments, she had registered with the Florida Medical Marijuana program and begun use of cannabis derivatives under medical direction. Products included an oral combination of CBD/THC 1:1 20 mg tincture used twice per day and 83 mg CBD oil taken along the gum line several times a day. Dosing of the tincture started with two drops placed on a teabag and infused in water to make a dilute brew. The CBD oil use was a single drop to start. Over time, the number of drops of each product used was titrated to benefit. She reported that use of the cannabinoids markedly minimized her stiffness and the intensity and frequency of spasm episodes. She denied any adverse side effects and reported feeling optimistic and calmer. She stopped taking the metaxalone and scheduled botulinum toxin injections to the paraspinal muscles only.

Comment

Paraneoplastic autoimmune disorders such as PSPS reflect antitumor immune responses against onconeural proteins that are autoantigens in the nervous system and are highly relevant to oncological and supportive/palliative care practice.
The diagnosis of PSPS can be readily mistaken for cancer progression or a neurodegenerative, infectious, demyelinating, or psychiatric condition.

As stress and anxiety worsen manifestations of PSPS, and associated anxiety and depressive mood are common and result in social disability, psychological assessment of PSPS is advised.

Study has shown that cognitive behavioral therapy decreases anxiety and improves rigidity and stiffness.

PSPS-related physical and psychological symptoms may respond favorably to early immunotherapy, treatment of the underlying cancer, and use of drugs that act on the GABAergic system (Table 1). However, management of the disorder is challenging and progression with compromise of quality of life is common. In their quest for relief, patients may seek alternative treatments. As U.S. state–sanctioned medical cannabis programs proliferate and include indications for cancer and neurologic conditions, cannabinoids are increasingly likely to be trialed by patients with paraneoplastic syndromes.

Table 1Treatments With GABAergic System, Immune-Modulating, or Suppressant Effects for Paraneoplastic Stiff Person Syndrome
Medication Dose/Day Mechanism of Action
Benzodiazepines GABA-A agonist
Diazepam 5–100 mg (1–6 mg divided doses), individualized and increased gradually over time
Clonazepam 5–100 mg (1–6 mg divided doses, individualized and increased gradually over time
Lorazepam 6–60 mg in divided doses, individualized and increased gradually over time
Baclofen 5–60 mg oral in divided doses

50–800 mcg/day intrathecal

 GABA-B agonist
Anticonvulsants GABAergic and other modes of action
Tiagabine 4–12 mg in divided or single dosing
Levetiracetam 2000 mg in divided doses
Gabapentin 3600 mg in divided doses
Others
Botulinum toxin Neuromuscular level inhibition
Tizanidine 4–36 mg in divided doses Central alpha-2 adrenergic agonist with presynaptic inhibitory effect
Dantrolene 100–200 mg in four divided doses Muscle relaxant
Immunomodulator or suppressants Dose
Rituximab Weekly infusion for one month

Or two doses of 350–500/m2 at two-week interval

Repeat dose for relapse

 Monoclonal antibody

Immune modulator
Intravenous immunoglobulin 2g/kg over two to five days Immunomodulator
Plasma exchange Removal of circulating autoantibodies, immune complexes, cytokines, and other inflammatory mediators
Cannabinoids Trials of cannabis derivatives individualized and increased gradually over time Presumptive effects on immune system, neuroinflammation, and CNS neuroprotection via CB2 and CB1 activation
GABA = γ-aminobutyric acid; CNS = central nervous system.

Cannabinoids exert their effects via the endocannabinoid system, which includes the cannabinoid receptors CB1 and CB2. CB1 receptors located in the CNS are involved in memory processing, motor function, appetite, and sensory perception. CB2 receptors are expressed in immune cells and are ascribed a role in modulating immune responses. Cannabinoids may affect the pathogenic mechanisms and symptoms of other autoimmune neurologic conditions with painful spasms, such as multiple sclerosis, owing to their ability to suppress neuroinflammation and exert neuroprotective effects in the CNS via activation of CB1 and CB2. Cannabinoid effects on the immune system may also be involved.

Given the autoimmune hypothesis of etiology and symptom overlap (spasticity and rigidity) with other cannabis-responding conditions, cannabinoids may benefit PSPS.

Our case suggests that state medical marijuana program–sanctioned THC/CBD products may provide relief for patients with refractory PSPS symptoms and additional confirmation is indicated.

Disclosures and Acknowledgments

The authors have nothing to disclose.

References

    • McKeon A.
    • Robinson M.T.
    • McEvoy K.M.
    • et al.
    Stiff-man syndrome and variants: clinical course, treatments, and outcomes.

    Arch Neurol. 2002; 69: 230-238

    View in Article 

    • Ariño H.
    • Hoftberger R.
    • Gresa-Arribas N.
    • et al.
    Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies.

    JAMA Neurol. 2015; 72: 874-881

    View in Article 

    • Rakocevic G.
    • Alexopoulos H.
    • Dalakas M.C.
    Quantitative clinical and autoimmune assessments in stiff person syndrome: evidence for a progressive disorder.

    BMC Neurol. 2019; 19: 1

    View in Article 

    • Baizabal-Carvallo J.F.
    • Jankovic J.
    Stiff-person syndrome: insights into a complex autoimmune disorder.

    J Neurol Neurosur Psych. 2014; 86: 840-848

    View in Article 

  5. Quality of life in stiff-person syndrome.

    Mov Disord. 2002; 17: 1064-1067

    View in Article 

    • Rabiei Z.
    Phytotherapy as a complementary medicine for multiple sclerosis.

    Turkish J Pharm Sci. 2019; 16: 2

    View in Article 

    • Vicente-Valor M.I.
    • Garcia-Llopis P.
    • Mejia Andujar L.
    • et al.
    Cannabis derivatives therapy for a seronegative stiff-person syndrome: a case report.

    J Clin Pharm Ther. 2013; 38: 71-73

    View in Article 

    • Ameli R.
    • Snow J.
    • Rakocevic G.
    • Dalakas M.C.
    A neuropsychological assessment of phobias in patients with stiff person syndrome.

    Neurology. 2005; 64: 1961-1963

    View in Article 

    • Morrisa L.L.
    • Dysch L.
    • Salkovskisa P.M.
    • Giffin N.
    Reducing excess stiffness in Stiff Person Syndrome using CBT: a case study.

    Neuro Rehab. 2014; 35: 627-631

    View in Article 

    • Filippini G.
    • Lasserson T.J.
    • Dwan K.
    • et al.
    Cannabis and cannabinoids for people with multiple sclerosis.

    Cochrane Database Syst Rev. 2019;

    View in Article 

Article info

Publication history

Published online: November 16, 2019

Identification

DOI: https://doi.org/10.1016/j.jpainsymman.2019.11.007

Copyright

© 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc.

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Key Message: This article describes a case of paraneoplastic stiff person syndrome and a novel treatment paradigm including medical cannabis. The outcomes suggest that state medical marijuana program-sanctioned THC/CBD products may provide relief for patients with refractory symptoms in this autoimmune neurologic condition. Further study is indicated.

© 2019 Published by Elsevier Inc. on behalf of American Academy of Hospice and Palliative Medicine

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