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Stiff-Person Syndrome

SMS

Stiff-Person syndrome is a rare disorder of the central nervous system in which progressive spasticity and muscle stiffness develops. Reduced GABA synthesis and impaired nerve serve signaling due to production and activity of autoantibodies is the underlying cause. Clinical criteria, EMG studies and identification of autoantibodies are necessary to make the diagnosis. GABA agonists, intravenous immunoglobulins, corticosteroids and immunomodulating agents such as rituximab are used in therapy.


Presentation

Slight variations exist across SPS subtypes, but axial muscle stiffness and episodic onset of spasms provoked by external stimuli are hallmarks of this condition [1]. Stiffness and rigidity are produced by activation of both agonists and antagonists, which may manifest with painful cramping, hyperlordosis, bending and walking difficulties, as well as frequent falling that may prone patients to use wheelchairs or canes [7]. The onset of spasms is precipitated by noxiously interpreted stimuli such as stress or unexpected loud noise. Moreover, psychiatric symptoms such as anxiety, depression and panic attacks are not uncommon, which is why SPS is often initially misdiagnosed as a psychiatric illness [7]. In paraneoplastic SPS, studies have shown that spasms confined to the extremities are more common, while additional findings include encephalopathy and myelopathy [9].

Fever
  • Here, we describe a 26-year-old woman who presented with psychosis, amnesia, rigidity and fever.[ncbi.nlm.nih.gov]
  • Rhodes has been sick for more than two years with symptoms that stumped doctors who originally suspected ailments ranging from meningitis to Rocky Mountain spotted fever.[fredhutch.org]
  • […] headache nausea and vomiting HIV may produce additional symptoms that include: nausea fever sore throat rash Infections such as Legionnaires’ disease, polio, and valley fever often cause symptoms such as: fever cough headache chest pain chills sore throat[healthline.com]
  • Stiff-person syndrome following West Nile fever. Archives of Neurology, 61 (6), 938-41.[naric.com]
Muscle Rigidity
  • SPS is characterized by fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli such as noise, touch, and emotional distress, which can set off muscle spasms.[ninds.nih.gov]
  • Stiff-person syndrome or Moersch-Woltmann is a very rare and disabling neurologic disorder characterized by muscle rigidity and episodic spasms involving axial and limb musculature.[ncbi.nlm.nih.gov]
Tachycardia
  • […] dysfunction with a 2:1 : ratio Clinical Stiffness of axial and appendicular muscles with intermittent superimposed painful muscle spasms precipitated by emotional or physical stress, low back pain, hyperlordosis, motor and gait defects, diaphoresis, tachycardia[medical-dictionary.thefreedictionary.com]
  • In addition to Stiff Person Syndrome, my sister has hypothyroidism, Postural Orthostatic Tachycardia Syndrome, chronic urticaria, and unspecified idiopathic peripheral neuropathy. My sister had symptoms for several years before she was diagnosed.[globalgenes.org]
  • She concomitantly developed a transient mild tachycardia (approximately 80 beats/min to approximately 105 beats/min) as well as hyperemia and hyperthermia isolated to the face and neck.[anesthesiology.pubs.asahq.org]
  • Tachycardia and hypertension are sometimes also present.Because of the spasms, patients may become increasingly fearful, require assistance, and lose the ability to work, leading to depression, anxiety, and phobias, including agoraphobia and dromophobia[en.wikipedia.org]
Dry Eyes
  • Despite the addition of oral prednisone, cyclosporine, and azathioprine, the patient's condition persisted with numerous filaments and severe dry eye.[ncbi.nlm.nih.gov]
Myopathy
  • ( G72.1 ) cramp and spasm ( R25.2 ) drug-induced myopathy ( G72.0 ) myalgia ( M79.1- ) stiff-man syndrome ( G25.82 ) Type 2 Excludes nontraumatic hematoma of muscle ( M79.81 ) Diagnosis Index entries containing back-references to G25.82 : Stiff-man syndrome[icd10data.com]
  • The same patient also developed a seizure disorder at age 14 years and subsequently neuropathy and myopathy at age 48 years, when diagnosed as having diabetes mellitus and SMS.[jamanetwork.com]
  • Intravenous immunoglobulin in patients with anti-GAD antibody-associated neurological diseases and patients with inflammatory myopathies: effects on clinicopathological features and immunoregulatory genes.[emedicine.com]
Muscle Cramp
  • One month later, the patient had an episode of sudden muscle cramps in her back, for which she was hospitalized. Investigations revealed a diagnosis of stiff person syndrome, positive for glutamic acid decarboxylase autoantibodies.[ncbi.nlm.nih.gov]
  • But life long athlete Tina Ceroni began having muscle cramps, spasms and rigidity in her legs. She thought she might be over training. Then the worst attack at a friends cottage landed her in hospital.[chch.com]
  • There are nights I will awaken with severe calf and muscle cramping where I am screaming in agony. I continuously have constant muscle activity in some form all the time.[rarediseaseday.org]
Muscle Twitch
  • RESULTS: The patient presented with recurrent episodes of vertigo with a pure peripheral pattern and with concomitant episodes of burning muscle pain, muscle twitching, weight gain and fatigue, worsening with tension or stress that also occurred in periods[ncbi.nlm.nih.gov]
  • By Jeff, United States, February 28, 2015 My first symptoms came back in August 2012, where I starting having muscle activity such as small spasms and fasiculations (muscle twitches). Soon, I was walking like a toy soldier with stiffness.[rarediseaseday.org]
  • It is a neurological condition that is characterized by progressive (progressive), muscle stiffness, painful muscle spasms and sometimes involuntary muscle twitching.[wieslab.se]
  • Her symptoms progressed over the next few years with more severe cramping, and longer episodes of painful spasms, muscle contractions, muscle twitches, and severe rigidity in all of her body.[ohfoundation.ca]
Myalgia
  • […] back-references to G25.82 : Type 1 Excludes: M62 ICD-10-CM Diagnosis Code M62 Other disorders of muscle 2016 2017 2018 2019 Non-Billable/Non-Specific Code Type 1 Excludes alcoholic myopathy ( G72.1 ) cramp and spasm ( R25.2 ) drug-induced myopathy ( G72.0 ) myalgia[icd10data.com]
Muscle Spasticity
  • When oral medication is inadequate to control muscle spasticity, intrathecal baclofen may be used.[ncbi.nlm.nih.gov]
  • Treating muscle spasticity with γ-aminobutyric acid (GABA) agonists and narcotics can lead to drug abuse and dependence. Muscle spasticity can fluctuate from hour to hour, abate with sleep, and get worse with emotional distress.[mdedge.com]
Vertigo
  • In rare cases, facial muscles, hands, feet, and the chest can be affected and unusual eye movements and vertigo occur. There are brisk stretch reflexes and clonus occurs in patients. Late in the disease's progression, hypnagogic myoclonus can occur.[en.wikipedia.org]
  • Stiffness and spasms may occur along with, before or after the development of other symptoms including vertigo, a lack of coordination of voluntary muscles (ataxia), and difficulty speaking (dysarthria).[rarediseases.org]
Stiff Gait
  • Stiff person syndrome (SPS) is a rare and disabling central nervous system disorder first described in 1956 and characterized by fluctuating rigidity and stiffness, gait impairment, and painful spasms of the axial and limb musculature.[ncbi.nlm.nih.gov]
  • The proximal legs can be involved in the process, and this is often only apparent on walking when the patient has a stiff gait.[jnnp.bmj.com]
Hyperreflexia
  • SYMPTOMS The most common signs are: - hyperreflexia reflexive integrity can be assessed via deep tendon reflexes (as well as resistance to passive stretch), grading it by a 0 to 4 scale (0 means complete absent reflexes, 4 indicates hyperactive reflexes[flipper.diff.org]
  • A woman was diagnosed in August 2005 as having SPS at age 48 years after presenting with progressive leg stiffness, hyperreflexia, and falls. Her reflexes were brisk but she had normal muscle tone and strength.[doi.org]
Abnormal Gait
  • The patients’ principal complaints included stiffness (ie, rigidity), primarily in the trunk muscles, that was superimposed by spasms, resulting in postural abnormalities, gait difficulties, and a tendency to ‘fall like a wooden man.’[redorbit.com]
Cranial Neuropathy
  • Associated symptoms revealed brainstem involvement (vertigo, diplopia, and cranial neuropathies) and dysautonomia (abnormal sweating and orthostatic hypotension). Anal manometry demonstrated incomplete relaxation of the anal sphincter.[ncbi.nlm.nih.gov]

Workup

A combination of clinical, laboratory and EMG studies are necessary to obtain a firm diagnosis of SPS. Clinical criteria comprise: 1) rigidity of the abdominal and thoracolumbar, as well as limb and trunk muscles; 2) simultaneous activation of agonist and antagonist muscles that is confirmed by either clinical observation or EMG studies; 3) presence of spasms that are triggered by environmental stimuli such as tactile sensations, noise or stress; and 4) exclusion of other neurological diseases that manifest with similar symptoms and signs [7]. As mentioned, EMG is imperative in supporting the findings during physical examination. Continuous motor unit activity (CMUA) at rest seen on EMG studies is virtually a patognomonic feature of this condition [2]. To confirm the diagnosis, however, anti-GAD or anti-amphiphysin antibodies should be identified and techniques such as immunohistochemistry, Western blot or radioimmunoassay are used [7].

Treatment

Various agents are used in symptomatic managements of SPS. GABAergic agents such as vigabatrin, gabapentin, baclofen, but also benzodiazepines such as diazepam are frequently used and usually show some degree of benefit [1] [5] [12]. The use of more potent therapeutic agents, such as intravenous immunoglobulins and plasmapheresis is necessary. Their use has shown variable results, however, showing much better outcomes in classical SPS compared to pareneoplastic forms [10]. Rituximab, an anti-CD20 antibody, has been recently introduced as a potentially effective agent in patients with SPS as initial reports showed promising results [11]. In addition to symptomatic therapy, appropriate management of psychiatric symptoms and physiotherapy are shown to be equally important for the overall quality of life [2].

Prognosis

The prognosis relies heavily on an early diagnosis, as significantly better outcomes are expected with early initiation of treatment. The course of the disease is unpredictable, as disability may be either mild or severe [6].

Etiology

SPS is divided into three subtypes: classical, paraneoplastic and SPS variants. Etiological mechanisms are of autoimmune origin across all types with some slight differences in target molecules. In classical SPS, symptoms appear due to synthesis of auto-antibodies against glutamic acid decarboxylase (GAD), the enzyme necessary for production of GABA, the main inhibitory neurotransmitter [3]. Approximately 60% of classic SPS patients have positive anti-GAD antibodies [3], while antibodies against glycine receptors, gephyrin, and GABA receptor-associated proteins have been identified in a smaller subset of patients [2]. On the other hand, paraneoplastic SPS is triggered by formation of anti-amphiphysin antibodies. Amphiphysin is a cytosolic protein that is involved in synaptic vesicle formation and endocytosis [8]. Impaired function of amphiphysin leads to failure of signal transmission at the synaptic cleft and the synthesis of antibodies can be most frequently encountered in patients suffering from malignancies of the breast, colon, lung and thymus [2]. Jerking-SPS, focal or segmental SPS and progressive encephalomyelitis with rigidity and myoclonus are recognized SPS subtypes that have similar etiological mechanisms as classical SPS, but their clarification requires further research, as some patients present without anti-GAD antibodies. The exact cause of antibody production in all forms of SPS, however, remains unknown.

Epidemiology

This condition is considered to be a rare entity in clinical practice and the vast majority of data relies on isolated case reports and single-center experiences. Across various studies, a strong association with other autoimmune diseases has been found. Certain reports found that almost 70% of patients had at least one autoimmune condition, with the most frequent being diabetes mellitus and autoimmune thyroid disease [9]. For some reason, a gender predilection toward females in a 2:1 ratio is observed [5], partly because paraneoplastic forms of SPS is most frequently associated with breast cancer, but only 5% of SPS cases belong to this group.

Sex distribution
Age distribution

Pathophysiology

Reduced activity of GABA is the main pathophysiological mechanism in the classical form of SPS. GABA is the main inhibitory neurotransmitter in the nervous system and its main effect on the musculoskeletal system is muscle relaxation. Under physiological circumstances, GABA is synthesized from glutamate through activity of glutamic acid decarboxylase (GAD), an enzyme situated in the cytoplasm of neurons [3]. For still unidentified reasons, autoantibodies against GAD are formed and suppress its activity, leading to deficiency of GABAergic effects in the CNS. As a result, progressive muscle stiffness because of practically absent relaxation and muscle rigidity occurs. Similar effects are achieved in paraneoplastic forms, were auto-antibodies against amphiphysin are identified [9]. Amphiphysin is a protein that exerts its function by promoting synaptic vesicle formation in the synaptic cleft and its reduced function leads to impaired endocytosis and reduced activity of neurotransmitters on the post-synaptic cleft [8].

Prevention

Despite the fact that the etiology of symptoms is almost completely determined, the exact cause of antibody formation remains unknown and prevention strategies currently do not exist. The focus on reducing morbidity from this condition relies heavily on the ability of the physician to make an early diagnosis and enable the patient to start treatment when the damage to the musculoskeletal and nervous system is not significant.

Summary

Stiff-Person syndrome (SPS) is a rare, but often severely debilitating disease of the central nervous system that is characterized by progressive rigidity and stiffness of various muscles, mainly of the axial skeleton, together with episodic appearance of spasms [1]. Three distinct subtypes have been described in literature [2]:

  • Classic SPS stems from the presence of autoantibodies against glutamic acid decarboxylase (GAD), one of the most important enzymes in synthesis of gamma-aminobutyric acid (GABA) [3]. GABA is the principal inhibitory neurotransmitter in neuronal tissue and reduced concentrations of this neurotransmitter throughout the central nervous system lead to profound muscle stiffness and rigidity [1]. Additionally, antibodies against GABA-A receptor-associated protein (GABARAP) and gephyrin and the glycine-α1 receptor, both influencing GABA activity, have been identified and can also contribute to CNS symptomatology [2] [4]. In these patients, the presence of diabetes mellitus type I or Hashimoto's thyroiditis is not uncommon, as they have shown to be more prone to developing another auto-immune disorder [3].
  • Paraneoplastic SPS is seen in approximately 5% of patients and is associated with concomitant malignant disease, most commonly breast cancer [10]. The pathogenesis includes formation of autoantibodies against amphiphysin I, a cytosolic protein normally found in very low concentrations in synaptic clefts but is abundant in malignant cells. In addition to breast cancer, the lungs, colon, thymus and lymphoma are described as potential causes [2].
  • SPS variants, such as focal or segmental SPS, jerking SPS and progressive encephalomyelitis with rigidity and myoclonus are described as additional subtypes [6], and their pathophsyiological mechanism is somewhat similar to that of classical SPS.

The clinical presentation, regardless of the type, invariably results in the appearance of stiffness that is most prominent in the muscles of the trunk and head (axial muscles) [1], but virtually any muscle group may be affected. Due to simultaneous contracture of agonists and antagonists, hyperlordosis and reduced bending capabilities, impaired gait and need for assistive devices such as canes or wheelchairs is often necessary [7]. Muscle spasms are often triggered by an external noxious stimulus, such as very loud sounds or emotional stress [7]. Depression, anxiety and panic attacks are frequent in these patients, as the condition presents as a significant burden both physically and mentally [2]. To make the diagnosis, electromyography (EMG) studies show typical continuous motor unit activity (CMUA) at rest, while serology testing for autoantibodies is used for confirmation [2]. Aside from EMG and serology, it is important to perform a detailed physical examination and obtain a comprehensive patient history that may reveal important findings regarding the presence of comorbidities such as diabetes or breast cancer. Therapeutic principles currently aim to alleviate symptoms through GABA agonists such as baclofen, gabapentin, vigabatrin, whereas corticosteroids, plasmapheresis and administration of intravenous immunoglobulins against autoantibodies are used as well [1]. Treatment efficacy and prognosis significantly depends on identifying SPS in its early stages, when the damage to CNS and other structures is minimal [4].

Patient Information

Stiff-Person syndrome (SPS) is a rare autoimmune disease of the central nervous system in which production of antibodies against enzymes and proteins involved in normal conduction of nerve signals. There are two main forms: the classical form, often diagnosed in patients who already have some other autoimmune disease such as diabetes mellitus type 1 or Hashimoto thyroiditis, and paraneoplastic SPS, diagnosed most frequently in patients who are suffering from various malignant diseases, most notably breast cancer. SPS is more common in women and patients of any age may be affected. In classical forms, symptoms arise due to reduced activity of molecules induce muscle relaxation (gamma-aminobutyric acid, known as GABA), which is caused by secretion of auto-antibodies that reduce the capacity for its formation. A similar end-result is seen in paraneoplastic SPS, where the structures that should carry the signals from nerve to nerve are insufficiently produced under the influence of auto-antibodies. This condition causes symptoms that can significantly impair the quality of life and daily activities, such as profound muscular stiffness and rigidity, together with episodic onset of muscle spasms. Usually, the muscles of the abdomen and trunk are affected and simultaneous activation of agonist and antagonist muscles (for example, the activation of abdominal and spinal muscles occurs at the same time) are considered as hallmarks of this disease. Spasms are usually provoked by environmental unpleasant stimuli such as loud noise or emotional stress and symptoms such as depression, panic attacks and anxiety are not uncommon. To make the diagnosis, the physician must conduct a full physical examination and confirm the presence of muscle stiffness and spasms. To support these findings, a test that evaluates muscle activity and nerve signaling called electromyography (EMG) is used, which will show continuous activity of neurons during rest, one of the main features of SPS. Additionally, identification of auto-antibodies is necessary to confirm SPS. Treatment focuses on overriding the effects of auto-antibodies by drugs that enhance activity of GABA, such as vigabartin, baclofen and several other, together with diazepam and corticosteroids. Administration of immunoglobulins and plasmapheresis, a method that aims to remove the auto-antibodies responsible for symptoms seen in this condition, are considered as mainstay of therapy, but their efficacy significantly varies from patient to patient. Physiotherapy and management of psychiatric symptoms is equally important in ensuring good long-term outcomes. It is important to emphasize that an early diagnosis may lead to markedly better effects of therapy, which is why physicians should have a high index of suspicion toward this disease in patients who have signs and symptoms that may suggest SPS, even though it is considered to be a rare disease.

References

Article

  1. Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome): report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin. 1956; 31(15):421-427.
  2. Geis C, Weishaupt A, Hallermann S, Grünewald B, Wessig C, Wultsch T, et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain. 2010 Nov;133(11):3166-3180.
  3. Butler MH, Hayashi A, Ohkoshi N, et al. Autoimmunity to gephyrin in Stiff-Man syndrome. Neuron. 2000 May; 26(2):307-312.
  4. Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology. 2008; 71(24):1955-1958.
  5. Buechner S, Florio I, Capone L. Stiff Person Syndrome: A Rare Neurological Disorder, Heterogeneous in Clinical Presentation and Not Easy to Treat. Case Reports in Neurological Medicine. 2015;2015:278065
  6. McKeon A, Robinson MT, McEvoy KM, et al. Stiff-Man Syndrome and Variants: Clinical Course, Treatments, and Outcomes. Arch Neurol. 2012;69(2):230-238.
  7. Dalakas MC. Advances in the pathogenesis and treatment of patients with stiff person syndrome. Curr Neurol Neurosci Rep. 2008;8(1):48-55
  8. Vasconcelos OM1, Dalakas MC. Stiff-person Syndrome. Curr Treat Options Neurol. 2003 Jan;5(1):79-90.
  9. Baker MR, Das M, Isaacs J, et al. Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry. 2005; 76(7):999-1001.
  10. Murinson BB. Stiff-person syndrome. Neurologist. 2004 May;10(3):131-137.
  11. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
  12. Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009 Mar;11(2):102-110.

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Last updated: 2019-07-11 20:57