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Everything About Stiff Person Syndrome (SPS) from A to Z

Discussion in 'Neurology' started by Egyptian Doctor, Jun 17, 2024.

  1. Egyptian Doctor

    Egyptian Doctor Moderator Verified Doctor

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    Stiff Person Syndrome

    Introduction
    Stiff Person Syndrome (SPS) is a rare, chronic neurological disorder characterized by progressive muscle stiffness and painful spasms. The syndrome, first described by Moersch and Woltman in 1956, is often associated with autoimmune conditions and can significantly impact a patient’s quality of life. The precise mechanisms behind SPS are still not fully understood, but it is believed to involve an autoimmune response affecting the central nervous system, particularly involving gamma-aminobutyric acid (GABA) pathways. This comprehensive guide aims to cover all aspects of SPS, including its etiology, epidemiology, clinical manifestations, diagnosis, treatment, and ongoing research.

    Etiology and Pathophysiology
    Autoimmune Mechanisms
    Stiff Person Syndrome is primarily considered an autoimmune disorder. Several antibodies have been implicated in its pathogenesis, the most significant being anti-glutamic acid decarboxylase (anti-GAD) antibodies. GAD is an enzyme crucial for the synthesis of GABA, the main inhibitory neurotransmitter in the central nervous system. The presence of these antibodies suggests an autoimmune attack on the GABAergic system, leading to reduced GABA activity, which results in increased muscle stiffness and spasms.

    1. Anti-GAD Antibodies:
      • Anti-GAD antibodies are found in approximately 60-80% of SPS patients. These antibodies interfere with GABA synthesis by targeting GAD, leading to a decrease in inhibitory neurotransmission and an increase in muscle tone and spasms.
    2. Other Autoantibodies:
      • In addition to anti-GAD, other autoantibodies such as anti-amphiphysin, anti-gephyrin, and anti-glycine receptor antibodies have been identified in some SPS patients. These antibodies target different components of the inhibitory synaptic transmission pathway, further contributing to the pathophysiology of the disease.
    Genetic Factors
    While SPS is primarily an autoimmune disorder, genetic factors may also play a role in its development. Certain human leukocyte antigen (HLA) types, particularly HLA-DR3 and HLA-DQw2, have been associated with an increased risk of developing SPS. These HLA types are also linked to other autoimmune diseases, suggesting a genetic predisposition to autoimmunity in SPS patients.

    Epidemiology
    Stiff Person Syndrome is an extremely rare disorder, with an estimated prevalence of about 1 in 1,000,000 people. It affects individuals of all ages, but the onset is most commonly observed in middle-aged adults, with a slight female predominance. SPS is often associated with other autoimmune diseases, such as type 1 diabetes mellitus, thyroiditis, and pernicious anemia, which may influence its epidemiological patterns.

    Clinical Manifestations
    The clinical presentation of SPS is characterized by a combination of muscle stiffness, spasms, and a range of other neurological symptoms. These manifestations can vary widely among patients, both in terms of severity and the specific muscles affected.

    Muscle Stiffness
    Muscle stiffness is the hallmark symptom of SPS. It typically begins insidiously and progresses over time, affecting the axial muscles (especially those of the trunk and abdomen) and the proximal limb muscles. This stiffness can lead to a rigid posture and difficulty in movement.

    1. Axial Muscle Stiffness:
      • Stiffness in the axial muscles can cause the classic “tin soldier” or “statue” appearance, where patients have a markedly rigid and upright posture. This stiffness can also impair respiratory function if the muscles of the thorax are involved.
    2. Proximal Limb Muscle Stiffness:
      • Stiffness in the proximal limb muscles, such as the shoulders and hips, can lead to significant disability, making it difficult for patients to perform everyday activities such as walking, dressing, and eating.
    Muscle Spasms
    Muscle spasms in SPS are often spontaneous, painful, and can be triggered by various stimuli, including sudden movements, loud noises, emotional stress, or physical touch.

    1. Types of Spasms:
      • Spasms can be focal or generalized and may vary in intensity and duration. They often affect the same muscles that are stiff, compounding the functional impairment.
    2. Triggers and Aggravating Factors:
      • Triggers for spasms are diverse and can include environmental factors (e.g., cold weather), emotional stress, or physical activities. These triggers can make it challenging for patients to avoid spasms and manage their condition effectively.
    Additional Neurological Symptoms
    Beyond muscle stiffness and spasms, SPS can present with a variety of other neurological symptoms, including:

    1. Exaggerated Startle Response:
      • Many patients with SPS exhibit an exaggerated startle response to unexpected stimuli, which can precipitate severe spasms and falls.
    2. Autonomic Dysfunctions:
      • Some patients experience autonomic dysfunctions, such as sweating abnormalities, orthostatic hypotension, and bowel or bladder dysfunction, due to the involvement of autonomic pathways.
    3. Cognitive and Emotional Symptoms:
      • Anxiety, depression, and other mood disorders are common in SPS patients, potentially exacerbated by the chronic nature of the disease and its impact on quality of life.
    Diagnosis
    Diagnosing SPS is challenging due to its rarity and the overlap of its symptoms with other neurological disorders. A comprehensive approach involving clinical evaluation, serological tests, and neurophysiological studies is essential.

    Clinical Evaluation
    The initial step in diagnosing SPS involves a thorough clinical evaluation, including a detailed medical history and physical examination. Key aspects to assess include:

    1. History of Symptoms:
      • Documenting the onset, duration, and progression of muscle stiffness and spasms, along with identifying potential triggers and aggravating factors.
    2. Physical Examination:
      • Observing the patient’s posture, gait, and range of motion. Assessing for muscle stiffness, spasms, and any signs of autonomic dysfunction.
    Serological Tests
    Serological tests are crucial for confirming the autoimmune nature of SPS. These tests typically include:

    1. Anti-GAD Antibodies:
      • Measuring the levels of anti-GAD antibodies in the blood. Elevated levels are strongly suggestive of SPS, although their absence does not exclude the diagnosis.
    2. Other Autoantibodies:
      • Testing for other autoantibodies, such as anti-amphiphysin, anti-gephyrin, and anti-glycine receptor antibodies, can provide additional diagnostic information.
    Neurophysiological Studies
    Neurophysiological studies can help differentiate SPS from other neurological disorders and provide insights into the underlying pathophysiology.

    1. Electromyography (EMG):
      • EMG can detect continuous motor unit activity, which is characteristic of SPS. This activity reflects the involuntary and persistent muscle contraction typical of the syndrome.
    2. Nerve Conduction Studies:
      • Nerve conduction studies can help rule out peripheral neuropathies and other conditions that might mimic SPS.
    Imaging Studies
    Imaging studies, such as MRI of the brain and spinal cord, are generally not diagnostic for SPS but can help exclude other neurological conditions that present with similar symptoms.

    1. MRI:
      • MRI may be used to rule out structural lesions or demyelinating diseases, such as multiple sclerosis, that could present with muscle stiffness and spasms.
    Differential Diagnosis
    Differentiating SPS from other neurological and musculoskeletal disorders is essential for accurate diagnosis and appropriate management. Conditions to consider include:

    1. Multiple Sclerosis:
      • MS can present with muscle stiffness and spasms but typically includes other signs such as optic neuritis, ataxia, and demyelinating lesions visible on MRI.
    2. Parkinson’s Disease:
      • Parkinson’s disease presents with rigidity and bradykinesia but is distinguished by tremor, particularly at rest, and a good response to dopaminergic medications.
    3. Tetanus:
      • Tetanus can cause muscle stiffness and spasms but is associated with a history of wound infection and lacks the chronic progressive nature of SPS.
    4. Spastic Paraparesis:
      • Conditions causing spastic paraparesis, such as hereditary spastic paraplegia or spinal cord lesions, can mimic SPS but often have different neurological findings and etiologies.
    Management
    Managing SPS requires a multidisciplinary approach, involving neurologists, immunologists, physiotherapists, and other healthcare professionals. The main goals are to reduce muscle stiffness and spasms, manage pain, and improve overall quality of life.

    Pharmacological Treatments
    Several pharmacological treatments are used to manage SPS, targeting different aspects of the disease.

    1. Benzodiazepines:
      • Benzodiazepines such as diazepam and clonazepam are the mainstay of treatment for SPS. They enhance GABAergic inhibition, reducing muscle stiffness and spasms. However, long-term use can lead to dependence and tolerance.
    2. Muscle Relaxants:
      • Baclofen, a GABA_B receptor agonist, is effective in reducing muscle tone and spasms. It can be administered orally or via an intrathecal pump for more severe cases.
    3. Immunomodulatory Therapies:
      • Immunomodulatory treatments, including intravenous immunoglobulin (IVIG), plasmapheresis, and rituximab, are used to target the underlying autoimmune processes. IVIG has shown significant benefits in reducing stiffness and improving mobility in SPS patients.
    4. Anticonvulsants:
      • Medications like gabapentin and pregabalin, which modulate neuronal excitability, can be beneficial in managing muscle spasms and neuropathic pain associated with SPS.
    5. Pain Management:
      • Pain management is crucial, involving a combination of pharmacological and non-pharmacological approaches. Analgesics, NSAIDs, and opioids may be used for pain relief, although the latter should be used with caution due to the risk of dependence.
    Physical and Occupational Therapy
    Physical and occupational therapy play a vital role in managing SPS. These therapies aim to improve mobility, reduce stiffness, and enhance daily functioning.

    1. Stretching and Strengthening Exercises:
      • Regular stretching exercises help maintain muscle flexibility and reduce stiffness. Strengthening exercises can improve overall muscle function and reduce the risk of falls.
    2. Postural Training:
      • Postural training can help patients maintain an upright posture and prevent complications such as kyphosis. This training often involves core strengthening and balance exercises.
    3. Assistive Devices:
      • Assistive devices, such as walkers, canes, and orthotics, can enhance mobility and safety for SPS patients, especially those with significant balance issues.
    4. Adaptive Strategies:
      • Occupational therapists work with patients to develop adaptive strategies for daily activities, making tasks such as dressing, eating, and bathing easier and safer.
    Psychological Support
    Given the chronic and debilitating nature of SPS, psychological support is essential. Patients often face significant emotional and psychological challenges, including anxiety, depression, and social isolation.

    1. Counseling and Therapy:
      • Counseling and psychotherapy can help patients cope with the emotional impact of the disease. Cognitive-behavioral therapy (CBT) is particularly effective in managing anxiety and depression.
    2. Support Groups:
      • Support groups provide a platform for patients to share experiences, receive support, and gain insights into managing their condition. These groups can be local or online, offering flexibility for participation.
    3. Stress Management:
      • Stress management techniques, such as mindfulness, meditation, and relaxation exercises, can reduce the frequency and severity of muscle spasms triggered by stress.
    Prognosis
    The prognosis of SPS varies widely among patients and depends on the severity of symptoms and response to treatment. SPS is a chronic condition with no known cure, but with appropriate management, many patients can achieve a good quality of life.

    1. Disease Progression:
      • SPS typically progresses slowly, with periods of stability interspersed with exacerbations. Early intervention and consistent management can help mitigate disease progression.
    2. Quality of Life:
      • Quality of life can be significantly impacted by SPS due to chronic pain, stiffness, and disability. However, comprehensive care and support can improve daily functioning and overall well-being.
    3. Complications:
      • Complications of SPS include severe disability, falls, fractures, and secondary infections due to reduced mobility. Regular monitoring and proactive management are essential to prevent these complications.
    Research and Future Directions
    Ongoing research aims to enhance the understanding and treatment of SPS. Key areas of focus include:

    1. Pathophysiological Studies:
      • Research into the underlying mechanisms of SPS, particularly the role of autoantibodies and genetic factors, is crucial. Advances in molecular biology and immunology may uncover new therapeutic targets.
    2. Innovative Treatments:
      • Developing novel treatments, such as targeted immunotherapies and gene therapies, holds promise for more effective management of SPS. Clinical trials are essential to evaluate the safety and efficacy of these treatments.
    3. Biomarker Development:
      • Identifying biomarkers for early diagnosis and monitoring disease progression can improve patient outcomes. Biomarkers can also help in tailoring personalized treatment approaches.
    4. Patient Registries and Databases:
      • Establishing patient registries and databases can facilitate large-scale studies and provide valuable data for research. These resources can help in understanding the epidemiology, natural history, and treatment outcomes of SPS.
    Conclusion
    Stiff Person Syndrome is a rare and complex neurological disorder that requires a comprehensive, multidisciplinary approach for diagnosis and management. Early detection, consistent treatment, and supportive care are essential to improve patient outcomes and quality of life. Advances in research and clinical practice continue to enhance our understanding of SPS and offer hope for more effective treatments in the future. With ongoing collaboration among healthcare professionals, researchers, and patients, the management of SPS will continue to evolve, providing better care and support for those affected by this challenging condition. stiff person syndrome.jpg
     

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  2. Egyptian Doctor

    Egyptian Doctor Moderator Verified Doctor

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    Additional Topics on Stiff Person Syndrome
    1. Impact on Daily Life:
      • Work and Employment: SPS can significantly impact a patient’s ability to work. Occupational adjustments, flexible working hours, and assistive technology can help maintain employment.
      • Social Relationships: The physical limitations and emotional burden of SPS can strain social relationships. Support from family, friends, and healthcare providers is crucial for maintaining social connections.
    2. Role of Caregivers:
      • Caregiver Support: Caregivers play a vital role in the management of SPS. Providing support and resources for caregivers can improve their well-being and enhance patient care.
      • Respite Care: Respite care options can provide temporary relief for caregivers, ensuring they have the opportunity to rest and recharge.
    3. Educational Resources:
      • Patient Education: Educating patients about their condition, treatment options, and self-management strategies is essential for empowering them to take an active role in their care.
      • Healthcare Provider Training: Training healthcare providers on the latest advances in SPS diagnosis and treatment can improve patient outcomes.
    4. Legal and Financial Considerations:
      • Disability Benefits: Patients with SPS may be eligible for disability benefits and financial assistance. Navigating these processes can be challenging, and support from social workers or patient advocates can be beneficial.
      • Insurance Coverage: Ensuring adequate insurance coverage for treatments, therapies, and assistive devices is crucial for managing the financial burden of SPS.
    5. Technological Innovations:
      • Telemedicine: Telemedicine offers a convenient way for patients with mobility issues to access healthcare services. It can facilitate regular follow-up appointments and consultations with specialists.
      • Wearable Technology: Wearable devices that monitor muscle activity and detect spasms can provide valuable data for managing SPS and adjusting treatments.
    6. Global Perspectives:
      • Epidemiological Studies: Understanding the global prevalence and distribution of SPS can provide insights into environmental and genetic factors contributing to the disease.
      • International Collaborations: Collaborations between researchers and healthcare providers across countries can accelerate the development of new treatments and improve patient care worldwide.
    7. Ethical Considerations:
      • Informed Consent: Ensuring informed consent for treatment and participation in clinical trials is essential. Patients should be fully aware of the potential risks and benefits of new therapies.
      • Privacy and Confidentiality: Protecting patient privacy and confidentiality is critical, especially when dealing with sensitive health information in research and clinical settings.
    8. Community Engagement:
      • Awareness Campaigns: Raising awareness about SPS through campaigns and educational programs can reduce stigma and promote early diagnosis and treatment.
      • Patient Advocacy: Advocacy groups play a vital role in supporting patients, influencing policy, and funding research. Engaging with these groups can amplify the voices of those affected by SPS.
    Pathophysiological Insights
    Understanding the intricate mechanisms underlying Stiff Person Syndrome is crucial for developing effective treatments. The condition primarily involves the central nervous system's GABAergic pathways, but recent research has uncovered more complex interactions at play.

    GABAergic System and Autoimmunity
    1. GABAergic Inhibition:
      • GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter in the brain. It reduces neuronal excitability by increasing the chloride ion influx into neurons, which hyperpolarizes the cell membrane and makes it less likely to fire an action potential.
      • In SPS, the reduction of GABAergic inhibition due to autoantibodies against GAD (glutamic acid decarboxylase) impairs this crucial balancing act, leading to increased muscle tone and spasms.
    2. Anti-GAD Antibodies Mechanism:
      • Anti-GAD antibodies directly target GAD, the enzyme responsible for converting glutamate to GABA. This reduction in GAD activity decreases GABA synthesis, resulting in lower levels of GABA in the central nervous system.
      • The exact mechanism by which these antibodies disrupt GAD function involves binding to active sites on the enzyme, preventing it from facilitating the conversion of glutamate to GABA.
    3. Other Autoantibodies:
      • Recent studies have identified other autoantibodies, such as anti-amphiphysin, anti-gephyrin, and anti-glycine receptor antibodies, which also play roles in synaptic transmission and neuronal signaling. Their presence in SPS patients suggests a broader autoimmune attack on inhibitory pathways in the nervous system.
    Genetic Predisposition
    1. HLA Associations:
      • Certain HLA (human leukocyte antigen) types, particularly HLA-DR3 and HLA-DQw2, have been linked to a higher risk of developing SPS. These HLA types are involved in the immune system's ability to present antigens and trigger immune responses, suggesting a genetic predisposition to autoimmunity in SPS patients.
    2. Familial Cases:
      • Although SPS is generally sporadic, familial cases have been reported, indicating a potential hereditary component. Studies of these families could provide insights into genetic mutations or variations that increase susceptibility to SPS.
    Advanced Diagnostic Techniques
    As the understanding of SPS evolves, so do the methods for diagnosing this rare and complex condition. Beyond the standard clinical evaluation, serological tests, and neurophysiological studies, advanced diagnostic techniques are being developed to improve accuracy and early detection.

    Molecular Diagnostics
    1. High-Sensitivity Serological Assays:
      • Newer serological assays with higher sensitivity and specificity are being developed to detect low levels of anti-GAD and other autoantibodies. These assays can improve the accuracy of SPS diagnosis, particularly in patients with atypical presentations.
    2. Genetic Testing and Sequencing:
      • Whole genome sequencing (WGS) and whole exome sequencing (WES) are advanced genetic testing methods that can identify genetic mutations and variations associated with SPS. These techniques provide comprehensive insights into the genetic factors contributing to the disease.
    Imaging Innovations
    1. Functional MRI (fMRI):
      • Functional MRI can measure brain activity by detecting changes in blood flow. In SPS patients, fMRI can identify areas of the brain with altered activity due to disrupted GABAergic inhibition, providing a more detailed understanding of the disease’s impact on neural circuits.
    2. Positron Emission Tomography (PET):
      • PET imaging can be used to visualize metabolic processes in the brain. PET scans with specific tracers for GABA receptors or other relevant biomarkers can help identify abnormalities in neurotransmitter function in SPS patients.
    Treatment Advances
    The treatment landscape for SPS is evolving with ongoing research and clinical trials exploring new therapeutic options. Current treatments focus on symptom management, but future therapies aim to address the underlying autoimmune mechanisms more effectively.

    Emerging Therapies
    1. Monoclonal Antibodies:
      • Monoclonal antibodies targeting specific immune cells or pathways involved in the autoimmune response are being investigated. For example, rituximab, which targets CD20-positive B cells, has shown promise in reducing autoantibody levels and improving symptoms in SPS patients.
    2. Gene Therapy:
      • Gene therapy approaches aim to correct genetic defects or modulate gene expression to restore normal GABAergic function. Although still in the experimental stages, gene therapy could offer a long-term solution for SPS by addressing its genetic and molecular roots.
    3. Stem Cell Therapy:
      • Stem cell therapy involves using stem cells to repair or replace damaged tissues and restore normal function. Research is exploring the potential of stem cell therapy to regenerate neurons and restore GABAergic inhibition in SPS patients.
    Personalized Medicine
    1. Biomarker-Guided Treatment:
      • The identification of biomarkers specific to SPS can enable personalized treatment approaches. Biomarkers can help predict disease progression, treatment response, and potential side effects, allowing for more tailored and effective therapies.
    2. Pharmacogenomics:
      • Pharmacogenomics studies how genetic variations affect a patient’s response to drugs. By understanding these variations, healthcare providers can select medications and dosages that are most effective for individual SPS patients, minimizing adverse effects and optimizing therapeutic outcomes.
    Long-Term Management and Prognosis
    Managing SPS is a lifelong commitment that involves addressing the physical, emotional, and social aspects of the disease. Long-term management strategies focus on maintaining functionality, reducing symptoms, and improving the overall quality of life.

    Comprehensive Care Plans
    1. Regular Monitoring:
      • Regular follow-up appointments with a multidisciplinary healthcare team are essential for monitoring disease progression, adjusting treatment plans, and managing complications. This team typically includes neurologists, immunologists, physiotherapists, and psychologists.
    2. Lifestyle Modifications:
      • Patients with SPS may benefit from lifestyle modifications, including stress management techniques, regular exercise, and a balanced diet. These changes can help improve physical and mental well-being and reduce the frequency and severity of symptoms.
    3. Patient and Caregiver Education:
      • Educating patients and caregivers about SPS, its symptoms, and management strategies is crucial for effective long-term care. Empowering patients with knowledge can enhance their ability to manage the disease and maintain independence.
    Addressing Complications
    1. Falls and Mobility Issues:
      • The muscle stiffness and spasms associated with SPS increase the risk of falls and mobility issues. Implementing safety measures at home, using assistive devices, and engaging in physical therapy can help mitigate these risks.
    2. Chronic Pain Management:
      • Chronic pain is a common issue in SPS patients. A multimodal approach to pain management, including medications, physical therapy, and complementary therapies such as acupuncture or massage, can provide relief and improve quality of life.
    3. Mental Health Support:
      • The psychological impact of SPS, including anxiety, depression, and social isolation, requires ongoing mental health support. Access to counseling, support groups, and mental health services is essential for addressing these challenges.
    Community and Advocacy
    Community support and advocacy play a crucial role in improving the lives of SPS patients. Advocacy groups, research organizations, and patient communities provide resources, support, and a platform for raising awareness about SPS.

    Patient Advocacy Groups
    1. Raising Awareness:
      • Advocacy groups work to raise awareness about SPS through educational campaigns, public events, and media outreach. Increased awareness can lead to earlier diagnosis, better treatment options, and more research funding.
    2. Support Networks:
      • Patient advocacy groups provide support networks for individuals with SPS and their families. These networks offer emotional support, practical advice, and a sense of community for those affected by the disease.
    3. Policy and Research Advocacy:
      • Advocacy groups engage in policy advocacy to influence healthcare policies and funding decisions. They also support research initiatives by funding studies, participating in clinical trials, and collaborating with researchers.
    Research and Collaboration
    1. International Research Networks:
      • Collaborations between researchers, healthcare providers, and advocacy groups across countries can accelerate the development of new treatments and improve patient care. International research networks facilitate the sharing of data, resources, and expertise.
    2. Patient Registries and Databases:
      • Establishing patient registries and databases is essential for conducting large-scale studies and understanding the epidemiology, natural history, and treatment outcomes of SPS. These resources provide valuable data for researchers and healthcare providers.
    3. Funding and Grants:
      • Securing funding and grants for SPS research is critical for advancing the understanding of the disease and developing new therapies. Advocacy groups and research organizations play a key role in raising funds and supporting research initiatives.
    Ethical Considerations
    Addressing the ethical considerations related to SPS diagnosis, treatment, and research is essential for ensuring patient rights and well-being.

    Informed Consent
    1. Patient Autonomy:
      • Ensuring that patients have the autonomy to make informed decisions about their treatment is a fundamental ethical principle. Patients should receive comprehensive information about their condition, treatment options, and potential risks and benefits.
    2. Clinical Trials:
      • Informed consent is crucial for participation in clinical trials. Researchers must provide clear and detailed information about the study’s purpose, procedures, risks, and potential benefits to participants.
    Privacy and Confidentiality
    1. Data Protection:
      • Protecting patient privacy and confidentiality is critical, especially when dealing with sensitive health information in research and clinical settings. Data protection measures should be in place to safeguard patient information.
    2. Genetic Testing:
      • Genetic testing raises specific ethical considerations regarding privacy and confidentiality. Patients should be fully informed about the implications of genetic testing and their rights to privacy and confidentiality.
    Conclusion
    Stiff Person Syndrome is a rare and complex neurological disorder that requires a comprehensive, multidisciplinary approach for diagnosis and management. Early detection, consistent treatment, and supportive care are essential to improve patient outcomes and quality of life. Advances in research and clinical practice continue to enhance our understanding of SPS and offer hope for more effective treatments in the future. With ongoing collaboration among healthcare professionals, researchers, and patients, the management of SPS will continue to evolve, providing better care and support for those affected by this challenging condition.
     

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