Paraneoplastic Stiff-person Syndrome Research Articles

Expanding the Understanding of Stiff-Person Syndrome: Insights from 17 Cases in India.

Stiff-person syndrome (SPS) is a rare and complex neurologic disorder characterized by progressive muscle stiffness, painful spasms, and gait difficulties. In this report, we describe a case of SPS who presented with a relapse while on maintenance immunosuppressive treatment. In addition, we review the literature of 16 previously reported cases of SPS from India, highlighting the diverse clinical features, comorbidities, treatment response, and relapse. The occurrence of paraneoplastic SPS emphasizes the need for early recognition and diagnosis.

Paraneoplastic stiff person syndrome with anti-amphiphysin antibodies presenting with pruritus as the initial manifestation: An unusual case

Paraneoplastic stiff person syndrome with anti-amphiphysin antibodies presenting with pruritus as the initial manifestation: An unusual case

Paraneoplastic Stiff Person Syndrome: Persistence of Symptoms is Common Despite Treatment of Underlying Malignancy (P18-1.001)

Paraneoplastic Stiff Person Syndrome: Persistence of Symptoms is Common Despite Treatment of Underlying Malignancy (P18-1.001)

Case Report: Breast cancer-associated paraneoplastic stiff person syndrome: anastrozole monotherapy insufficient for symptom improvement

Stiff person syndrome (SPS) is a rare clinical disorder presenting with progressive muscle stiffness and painful spasms. Its ill-defined mechanism and variable presentation make diagnosis a challenge, though it is associated with a range of specific auto-antibodies. One particular antibody, anti-amphiphysin, is found in the presence of breast or lung malignancy and leads to a disorder termed paraneoplastic SPS (PSPS). Our patient, an 83-year-old woman, presented with bilateral leg weakness, spasms, and left clubfoot over a period of three months. She also reported a lump in her left breast for which she had not sought treatment over the past 10 years. Her ankle radiograph was negative for fractures and dislocations, while an MRI of the left leg was negative for plexopathies. Electromyography was suggestive of an SPS disorder and a positive anti-amphiphysin test indicated a diagnosis of PSPS. Her symptoms were managed with baclofen, diazepam, and five cycles of therapeutic plasma exchange (TPEX) over 10 days. Breast imaging revealed a 4.5-cm left breast lesion, later biopsy-confirmed as invasive ductal carcinoma (ER+, PR+, HER2−). The patient declined definitive surgical management, opting instead for once-daily anastrozole 1 mg as hormonal therapy. This regimen was not sufficient to lead to symptomatic improvement over a period of more than 30 days, and the patient expired less than 45 days after discharge. To our knowledge, this is the first case of PSPS to be treated in this manner. Our report illustrates that conservative management with anastrozole monotherapy was not sufficient to lead to symptomatic improvement in this form of paraneoplastic syndrome, suggesting the need for more aggressive pharmacological or definitive surgical intervention in order to produce symptom improvement and/or resolution.

STIFF PERSON SYNDROME (SPS) THE IMPORTANCE OF EXTENSIVE PHYSICAL EXAMINATION

Stiff Person Syndrome (SPS) is a rare condition with a prevalence of one to two cases per million and an incidence of one case per year. Characterized by progressive muscle stiffening, rigidity and spasm, mainly involve the axial muscles, resulting in severely impaired ambulation. The pathogenesis is not that clear. Classic SPS presents with extreme and persistent rigidity and stiffness of truncal and proximal limb muscles, significant lumber/cervical lordosis resulting from simultaneous actions of opposing paraspinous muscles are the hallmark. Wide and unsteady gait (Frankenstein’s gait) resulting from stiff muscles increases the risk of fall and fracture. Patient’s ADLs get severely restricted progressively. Startle reflex which is a superimposed episodic muscle spasm precipitated by sudden movement, noise, or emotional upset is a sensitive and specific feature of SPS and can be visible and palpable. Autonomic dysfunctions are common and are common cause of death in patients with SPS. In cases of partial SPS, we can find that truncal muscles are spared and limb muscles are affected, hence the term stiff-limb syndrome is used sometimes. Can involve a limb or focal part of a limb. As for treatment, symptom control and improving mobility and overall functionality is the primary target. High dose benzodiazepine is the best initial treatment. Those who are refractory can be benefit from Baclofen, IVIG, Plasma exchange, biological agent, e.g. Rituximab. Treatment of primary malignancies in paraneoplastic SPS can achieve remission. Keywords: Stiff Person Syndrome, clinical features, diagnosis and treatment.

A Case of Paraneoplastic Stiff-person Syndrome with Advanced Breast Cancer

Stiff-person syndrome（SPS）は，特徴的な筋硬直および有痛性痙攣により進行性に四肢軀幹筋の運動障害を引き起こす極めて稀な疾患であり，診断に苦慮することがある．SPSでは抗GAD抗体や抗amphiphysin抗体などの自己抗体が証明される場合があり，これらの抗体による中枢神経系でのGABA作動性ニューロンの障害が推測されている．今回われわれは，進行期乳がん患者に発症した傍腫瘍性SPSの症例を経験したので報告する．【症例】患者は52歳の女性で，両側肺転移，両側がん性胸膜炎，肝転移，がん性腹膜炎，両側卵巣転移を伴う進行期乳がんと診断された．全身状態不良のため抗がん治療の適応はなく，緩和ケア病棟入院にて酸素投与や胸腹水ドレナージを行ったが，嚥下障害に始まり筋硬直による上肢の運動障害や歩行障害が急速に進行し，脳神経内科にて傍腫瘍性SPSと診断された．ジアゼパム投与で若干効果が認められたが，傾眠となり投与量調整に難渋した．

Anti-glutamic acid decarboxylase antibody positive neurological syndromes.

A rare kind of antibody, known as anti-glutamic acid decarboxylase (GAD) autoantibody, is found in some patients. The antibody works against the GAD enzyme, which is essential in the formation of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter found in the brain. Patients found with this antibody present with motor and cognitive problems due to low levels or lack of GABA, because in the absence or low levels of GABA patients exhibit motor and cognitive symptoms. The anti-GAD antibody is found in some neurological syndromes, including stiff-person syndrome, paraneoplastic stiff-person syndrome, Miller Fisher syndrome (MFS), limbic encephalopathy, cerebellar ataxia, eye movement disorders, and epilepsy. Previously, excluding MFS, these conditions were called ‘hyperexcitability disorders’. However, collectively, these syndromes should be known as “anti-GAD positive neurological syndromes.” An important limitation of this study is that the literature is lacking on the subject, and why patients with the above mentioned neurological problems present with different symptoms has not been studied in detail. Therefore, it is recommended that more research is conducted on this subject to obtain a better and deeper understanding of these anti-GAD antibody induced neurological syndromes.

Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition

Stiff-person syndrome is the prototype of a central nervous system disorder with autoantibodies targeting presynaptic antigens. Patients with paraneoplastic stiff-person syndrome may harbour autoantibodies to the BAR (Bin/Amphiphysin/Rvs) domain protein amphiphysin, which target its SH3 domain. These patients have neurophysiological signs of compromised central inhibition and respond to symptomatic treatment with medication enhancing GABAergic transmission. High frequency neurotransmission as observed in tonic GABAergic interneurons relies on fast exocytosis of neurotransmitters based on compensatory endocytosis. As amphiphysin is involved in clathrin-mediated endocytosis, patient autoantibodies are supposed to interfere with this function, leading to disinhibition by reduction of GABAergic neurotransmission. We here investigated the effects of human anti-amphiphysin autoantibodies on structural components of presynaptic boutons ex vivo and in vitro using electron microscopy and super-resolution direct stochastic optical reconstruction microscopy. Ultrastructural analysis of spinal cord presynaptic boutons was performed after in vivo intrathecal passive transfer of affinity-purified human anti-amphiphysin autoantibodies in rats and revealed signs of markedly disabled clathrin-mediated endocytosis. This was unmasked at high synaptic activity and characterized by a reduction of the presynaptic vesicle pool, clathrin coated intermediates, and endosome-like structures. Super-resolution microscopy of inhibitory GABAergic presynaptic boutons in primary neurons revealed that specific human anti-amphiphysin immunoglobulin G induced an increase of the essential vesicular protein synaptobrevin 2 and a reduction of synaptobrevin 7. This constellation suggests depletion of resting pool vesicles and trapping of releasable pool vesicular proteins at the plasma membrane. Similar effects were found in amphiphysin-deficient neurons from knockout mice. Application of specific patient antibodies did not show additional effects. Blocking alternative pathways of clathrin-independent endocytosis with brefeldin A reversed the autoantibody induced effects on molecular vesicle composition. Endophilin as an interaction partner of amphiphysin showed reduced clustering within presynaptic terminals. Collectively, these results point towards an autoantibody-induced structural disorganization in GABAergic synapses with profound changes in presynaptic vesicle pools, activation of alternative endocytic pathways, and potentially compensatory rearrangement of proteins involved in clathrin-mediated endocytosis. Our findings provide novel insights into synaptic pathomechanisms in a prototypic antibody-mediated central nervous system disease, which may serve as a proof-of-principle example in this evolving group of autoimmune disorders associated with autoantibodies to synaptic antigens.

Stiff Person Syndrome: A Rare Neurological Disorder, Heterogeneous in Clinical Presentation and Not Easy to Treat.

Background. Stiff person syndrome (SPS) is a rare neurological disorder characterized by progressive rigidity of axial and limb muscles associated with painful spasms. SPS can be classified into classic SPS, paraneoplastic SPS, and SPS variants. Its underlying pathogenesis is probably autoimmune, as in most cases antibodies against glutamic acid decarboxylase (GAD) are observed. Similarly, paraneoplastic SPS is usually linked to anti-amphiphysin antibodies. Treatment is based on drugs enhancing gamma-aminobutyric acid (GABA) transmission and immunomodulatory agents. Case Series. Patient 1 is a 45-year-old male affected by the classic SPS, Patient 2 is a 73-year-old male affected by paraneoplastic SPS, and Patient 3 is a 68-year-old male affected by the stiff limb syndrome, a SPS variant where symptoms are confined to the limbs. Symptoms, diagnostic findings, and clinical course were extremely variable in the three patients, and treatment was often unsatisfactory and not well tolerated, thus reducing patient compliance. Clinical manifestations also included some unusual features such as recurrent vomiting and progressive dysarthria. Conclusions. SPS is a rare disorder that causes significant disability. Because of its extensive clinical variability, a multitask and personalized treatment is indicated. A clearer understanding of uncommon clinical features and better-tolerated therapeutic strategies are still needed.

Non-stiff anti-amphiphysin syndrome: Clinical manifestations and outcome after immunotherapy

Amphiphysin antibody causes paraneoplastic stiff-person syndrome and can also result in a variety of neurological manifestations. Here, we investigated the clinical spectrum of 20 patients with non-stiff anti-amphiphysin syndrome and their responses to immunotherapy. The most common neurological manifestation was limbic encephalitis (n=10), followed by dysautonomia (n=9), and cerebellar dysfunction (n=6). Cancer was detected in only seven patients. Intravenous immunoglobulin or steroid treatment was effective in most patients, but three improved only after rituximab treatment. Our study suggests that anti-amphiphysin syndrome can manifest as non-stiff encephalomyelitis and is only partially associated with cancer. Active immunotherapy, including rituximab, would be beneficial.

2. Stiff person syndrome

Background Stiff person syndrome (SPS) is a rare, insidiously progressive disease of central nervous system characterized by axial and limb rigidity with superimposed stimulus-sensitive spasms. SPS can be divided to classical generalized form, stiff limb syndrome, jerking SPS and progressive encephalomyelitis with rigidity and myoclonus (PERM). The incidence of SPS and its variant is about 1 per million in European population. Methods In this study of retrospective design we have evaluated all patients with muscle overactivity syndromes investigated in our EMG laboratory in last 6 years. Patient with SPS were further described and demographic data, EMG findings, laboratory results, auxiliary methods, therapy and improvement/progression were analyzed. Results During 6-year period (2007–2013) 5 patients with SPS were diagnosed and treated in Department of Neurology, PKN. There were 3 women and 2 men, 22–65 yrs. In 3 patients we were able to find a provoking factor (2 infectious diseases – tick-born encephalitis, herpes zoster; one patient was exposed to solvents during longer work in a garage). In all patients EMG was characterized by continuous muscle activity (normal motor unit potential), 3 with higher voltage of F-waves, in a woman constant retroflexion reaction. In 2 patients we found very high titers of anti-GAD in serum, in 1 in cerebrospinal fluid, and in another women increased titer of anti-amphiphysin. All patients were treated with immunosupression (steroids and later azathioprine or cyclosporin A), 3 patients treated with plasma exchange, 2 with high doses of intravenous immunoglobulins, and all by baclofen. Paraneoplastic SPS were in 2 (thymoma, multiple myeloma) and autoimmune type of SPS were in 3 patients. Conclusion SPS is one of the orphan diseases, which diagnosis and treatment demand experienced staff in EMG lab, broad spectrum of immunological laboratory methods, and neurologic intensive care unit for monitoring and treatment.

Evidence of T-cell mediated neuronal injury in stiff-person syndrome with anti-amphiphysin antibodies

Paraneoplastic stiff-person syndrome (SPS) has been associated with antibodies against amphiphysin. Current evidence supports a pathogenic role for anti-amphiphysin antibodies. A 74-year-old female was diagnosed with amphiphysin-associated paraneoplastic stiff-person syndrome and associated encephalomyelitis. She had initial response to IVIG, however her symptoms worsened after two months and were resistant to further treatment. Subsequently the patient died and a post-mortem was performed. Neuropathology revealed perivascular and parenchymal lymphocytic infiltrates, with neuronophagia mediated by CD8+ T cells and microglia in brainstem, spinal cord, and mesial temporal lobe structures. These findings suggest a pathogenic role of cytotoxic CD8+ T-cells, with potential implication for therapy of future patients.

Paraneoplastic stiff person syndrome associated with colon cancer misdiagnosed as idiopathic Parkinson’s disease worsened after capecitabine therapy

ObjectivesTo refresh clinical diagnostic dilemmas in patients presenting with symptoms resembling to those of parkinsonism, to report rare association of colon cancer and paraneoplastic stiff person syndrome (SPS), and to draw attention on the possible correlation of capecitabine therapy with worsening of paraneoplastic SPS.MethodsCase report of the patient with paraneoplastic SPS due to colon cancer that was misdiagnosed as idiopathic Parkinson’s disease (iPD), whose symptoms worsened after beginning adjuvant capecitabine chemotherapy.ResultsWe describe a 55-year-old woman with subacute onset of symmetrical stiffness and rigidity of the truncal and proximal lower limb muscles that caused lower body bradykinesia, gait difficulties, and postural instability. Diagnose of iPD was made and levodopa treatment was initiated but failed to provide beneficial effect. Six months later, colon cancer was discovered and the patient underwent surgical procedure and chemotherapy with capecitabine thereafter. Aggravation of stiffness, rigidity, and low back pain was observed after the first chemotherapy cycle and capecitabine was discontinued. Furthermore, levodopa was slowly discontinued and low dose of diazepam was administered which resulted in partial resolution of the patient’s symptoms.ConclusionParaneoplastic SPS is rare disorder with clinical features resembling those of parkinsonian syndrome and making the correct diagnosis remains a challenge. The diagnosis of parkinsonian syndrome should be re-examined if subsequent examinations discover an associated malignant process. Although it remains unclear whether the patients with history of SPS are at the greater risk for symptoms deterioration after administration of capecitabine, clinicians should be aware of capecitabine side effects because recognition and appropriate management can prevent serious adverse outcomes.

Lower Extremity Predominant Stiff-Person Syndrome and Limbic Encephalitis With Amphiphysin Antibodies in Breast Cancer

A 54-year-old woman presented with several weeks of psychiatric symptoms, partial-onset seizures, and painful spasms of the lower extremities. On examination, she exhibited severe stiffness and intermittent extensor spasms of the lower extremities. Magnetic resonance imaging of the brain showed T2 hyperintensity in the left temporal lobe with enhancement after gadolinium administration on T1-weighted images. Amphiphysin antibodies were present in the serum. Radiographic screening for malignancy disclosed a metastatic breast cancer. The case is a unique example of amphiphysin autoimmunity, illustrating the possibility of paraneoplastic stiff-person syndrome and limbic encephalitis coexisting in a patient with a "classical" presentation of stiff-person syndrome confined to the lower extremities.

Successful 'passive transfer' of paraneoplastic stiff person syndrome with antibodies to an intracellular antigen

This is an exciting time for neuroimmunology. Over the last 10 years, several clinical syndromes have been shown to associate closely with highly specific autoantibodies directed at neuronal or glial antigens, including voltage-gated potassium channel complexes [now known to contain two proteins, Lgi1 and Caspr2 that are the main targets (Irani et al. , 2010; Lai et al. , 2010)], aquaporin-4 (Lennon et al. , 2005) and a miscellany of ionotrophic and metabotropic receptors, most importantly N -methyl-d-aspartate (NMDA) receptors (Dalmau et al. , 2008). The clinical syndromes may involve the limbic system, basal ganglia, cerebellum, brainstem, optic nerves or spinal cord (Graus et al. , 2010). Unlike the well-established antibody-mediated diseases of the peripheral nervous system or neuromuscular junction, myasthenia gravis and Lambert–Eaton myasthenic syndrome, in which the pathogenic roles of the antibodies were demonstrated relatively easily by passive transfer (Toyka et al. , 1975; Lang et al. , 1983), similar experiments with CNS disorders are technically more demanding. Some headway has been made in neuromyelitis optica by demonstrating that systemic delivery of purified aquaporin-4 antibody-positive immunoglobulin, that binds predominantly to astrocytes, results in neuromyelitis optica-like inflammatory lesions in the brain or spinal cord of mice, if the blood–brain barrier is compromised by encephalotogenic T cells (Bennett et al. , 2009; Bradl et al. , 2009; …

Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition

Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.

Stiff-person syndrome

The stiff-person syndrome (SPS) is a rare neurologic disorder of uncertain cause, characterized by severe and incapacitating axial and proximal limb rigidity due to continuous motor unit activity. Rigidity is often enhanced by anxiety, sudden movements or external stimuli causing intermittent painful muscle spasms, often leading to skeletal deformity. Variants of this disorder include focal involvement of one limb (“stiff-limb syndrome”), or additional neurological symptoms suggestive of involvement of subcortical gray matter (“progressive encephalomyelitis with rigidity and myoclonus”) (PEWR) and occasionally secondary to malignant disease (paraneoplastic SPS). Antineuronal antibodies often associated with other auto-immune diseases are characteristic features of this disorder. The disease follows a progressive, unremitting course, resulting in pronounced disability, if left untreated. This unusual syndrome was first described by Moersch and Woltman in 1956 [1]. The authors coined the term “stiff-man syndrome” in reporting 14 patients with clinical features of progressive fluctuating muscular rigidity and spasms. Their first case, a 49year-old man, initially complained of a feeling of tightness of the neck musculature of variable occurrence. Over a period of 4 years this disorder progressively affected the muscles of the shoulder, back, abdomen, and thighs, causing the muscles to appear stiff and “board-like”. Continuous muscle contraction causing pronounced stiffness of the axial and limb muscles forced the patient to walk in a peculiar way that was both slow and awkward. Voluntary movement or passive displacement of the limbs triggered prolonged and painful muscle spasms. If severe enough, the spasms caused postural instability and falls. In the words of the authors, the patient would fall like a “wooden man”. The additional 13 patients in the original report were similar in all respects. The clinical features of this previously unreported condition were described in detail in Moersch and Woltman’s paper. No other signs of central or peripheral nervous system involvement were

Stiff person syndrome associated anti-amphiphysin antibodies reduce GABA associated [Ca 2+] i rise in embryonic motoneurons

Autoantibodies to the synaptic protein amphiphysin play a crucial pathogenic role in paraneoplastic stiff-person syndrome. Impairment of GABAergic inhibition is the presumed pathophysiological mechanism by which these autoantibodies become pathogenic. Here we used calcium imaging on rat embryonic motor neurons to investigate whether antibodies to amphiphysin directly hinder GABAergic signaling. We found that the immunoglobulin G fraction from a patient with stiff-person syndrome, containing high titer antibodies to amphiphysin and inducing stiffness in rats upon passive transfer, reduced GABA-induced calcium influx in embryonic motor neurons. Depletion of the anti-amphiphysin fraction from the patient's IgG by selective affinity chromatography abolished this effect, showing its specificity for amphiphysin. Quantification of the surface expression of the Na +/K +/2Cl 2− cotransporter revealed a reduction after incubation with anti-amphiphysin IgG, which is concordant with a lower intracellular chloride concentration and thus impairment of GABA mediated calcium influx. Thus, anti-amphiphysin antibodies exert a direct effect on GABA signaling, which is likely to contribute to the pathogenesis of SPS.

UNEXPECTED BENEFIT OF PROPOFOL IN STIFF-PERSON SYNDROME

Stiff person syndrome (SPS) is a rare autoimmune disorder characterized by severely increased axial muscular tone with superimposed “progressive fluctuating muscular rigidity and spasms,” despite an otherwise normal neurologic examination.1 An association with autoimmune disease was noted early on, and in 1988 high titers of autoantibodies directed against glutamic acid decarboxylase (GAD) were found in patients with SPS.2 GAD catalyzes the rate-limiting step in the synthesis of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter of the CNS. These observations, along with the known beneficial effects of drugs that enhance GABAergic neurotransmission, underlie the current concept of SPS as an immune-mediated pathologic impairment of central inhibition. This concept is supported by various electrophysiologic studies.3 SPS has also been described as a paraneoplastic syndrome in association with several types of tumors, including breast and small cell lung cancer. Paraneoplastic SPS may be associated with anti-GAD antibodies, as well as amphiphysin 1, gephyrin, or Ri antibodies.4 Although the pathophysiology of non-paraneoplastic SPS is incompletely understood, effective treatments include immunomodulating therapies and drugs that enhance GABAergic neurotransmission. Unfortunately, these treatments may lose …

Progressive encephalomyelitis with rigidity and myoclonus in an 81-year-old patient

We present the case of an 81-year-old female with severe rigidity, stiffness and superimposed muscle spasms that represents the oldest reported patient with progressive encephalomyelitis with rigidity and myoclonus. Two associated autoimmune disorders (diabetes mellitus and Hashimoto's thyoiditis) were recently diagnosed. A paraneoplastic origin was excluded. The spectrum of differential diagnoses including classic Stiff-Person syndrome and paraneoplastic Stiff-Person syndrome is discussed.