The Interesting Case
Background !
The stiff person syndrome (SPS) is a rare autoimmune neurological disorder, featuring progressive stiffness and rigidity of the axial muscles (Rakocevic G et al. Muscle Nerve 2012; 45: 623). In most cases SPS is an idiopathic disease with a suspected prevalence of approximately one per million (Ciccoto G et al. Neurol Clin. 2013; 31: 319). However, in 5 – 10 % of cases it presents as paraneoplastic disease (Alexopoulos H et al. Eur J Clin Invest 2012; 40: 1018), mostly in patients with small-cell lung carcinoma, breast carcinoma and melanoma (Pittock SJ et al. Ann Neurol 2005; 58: 96). Autoantibodies against amphiphysin, and gephyrin muscles (Rakocevic G et al. Muscle Nerve 2012; 45: 623) are strongly associated with the secondary paraneoplastic form. While idiopathic stiff person syndrome usually develops over months and features typical GAD (glutamic acid decarboxylase) antibodies (Jung YJ et al. J Mov Disord. 2014; 7: 19), the paraneoplastic version features a subacute onset (Byrne TN et al. N Engl J Med. 2012; 367: 851). Clinical presentation ranges from stiffness and spasms in the thoracoabdominal spine and proximal legs, to a change in posture and gait, worsening chronic pain and even paralysis.
Case Description !
Without a significant previous medical history, a 36-year-old Caucasian female was admitted at an outside hospital and reported to be afraid to walk without help. Initially psychological features dominated the clinical symptoms and led to the misdiagnosis of a psychogenic movement disorder. Subsequently she developed progressive muscle rigidity and stiffness of the legs and lower back paired with recurring painful spasms. This condition developed over a few weeks, and led to an inability to walk. In fact, the patient was wheelchair bound only a few weeks after initial presentation. Since the beginning of the symptoms, the patient reported that she was extremely sensitive to noise. In the clinical examination the patient presented exaggerated re-
flexes of the lower extremities and spasms as well as rigidity and stiffness of the trunk. Spasm could be also triggered by contact or noise. The gait was slow and wide to improve balance. Abnormalities of the cranial nerves were not observed. The facial and thoracic muscles were not affected.
Diagnostics !
Laboratory workup including complete blood count/white cell differentiation, electrolytes, minerals and glucose, waste products, enzymes and proteins (including C-reactive protein) was unremarkable except a 9-fold elevation of creatine kinase (1574 U/I). Tumor markers (CEA; CA 19 – 9), hormones (including thyroid stimulating hormones and antibodies) were negative. Magnetic resonance imaging (MRI) studies of the brain and the spinal cord as well as analysis of the cerebrospinal fluid revealed no abnormality. GAD (glutamic acid decarboxylase) antibodies were not detected in the cerebral spinal fluid or in the serum of the patient. Electromyography showed no reflex-myoclonus and nerve conduction velocities where nonconclusive, but both were ruled as non-diagnostic as the patient received benzodiazepine therapy at the time of testing. After treatment with diazepam at a dosage of 5 mg three times a day was initiated, symptoms improved promptly. The patient immediately underwent plasmapheresis therapy with 5 cycles. Unfortunately symptoms did not stabilize after plasmapheresis, thus treatment with diazepam had to be continued in the initial dosage. In order to protect the patient’s kidneys and clear the very high levels of creatine kinase, plasmapheresis was ordered and the patient received a Shaldon-catheter through the right internal jugular vein. Post-interventional chest Xray was normal. Following dialysis, creatine kinase normalized and continuous extensive monitoring of the patient’s laboratory values did not show relevant abnormalities. The patient’s symptoms persisted however and she received the working hypothesis of stiff person syndrome, although it was unclear whether it was idiopathic or paraneoplastic.
Contrast-enhanced whole-body computed tomography (CT) performed elsewhere in the arterial and portal venous phase was evaluated as unsuspicious. At admittance to a university breast center, the CT scan was re-evaluated and a spiculated inhomogeneous mass was identified in the left breast which was missed at initial diagno" Fig. 1). Subsequent complementary sis (● breast diagnosis including clinical examination and medio-lateral oblique digital full-field mammography of both breasts (Novation®, Siemens, Erlangen, Germany) was performed. Breast tissue density was classified as extremely dense according to ACR criteria and no suspicious lesion could " Fig. 2). Additionally ultrabe identified (● sonography (Acuson Antares®, Siemens, Erlangen, Germany) with a 14 MHz linear transducer was performed by a breast ima-
Fig. 1 Oval mass (white circle) in the left breast with higher densities than surrounding breast tissue in the contrast-enhanced CT scan.
Fig. 2 Digital full-field mammography of both breasts in mediolateral oblique projection. No suspicious lesion could be identified in the extremely dense tissue.
Dankerl P et al. Stiff Young Woman … Fortschr Röntgenstr 2015; 187: 589–590 · DOI http://dx.doi.org/10.1055/s-0034-1398829
Downloaded by: Universite Laval. Copyrighted material.
Stiff Young Woman
589
The Interesting Case
Fig. 3 Ultrasonography of the left breast with an 18 × 7 mm oval mass lesion (arrows) at 11 o’clock, 8 cm distant from the nipple. The mass lesion is isoechoic with respect to the surrounding normal fatty breast tissue (arrowhead) and to the pectoral muscle (asterix) which makes it difficult to differentiate it from normal findings.
ging expert. Sonography demonstrated an 18 × 7 mm mass lesion with an echogenicity similar to normal fatty breast tissue " Fig. 3). It was located at 11 o’clock 8 cm (● from the nipple in the left breast and matched with the mass lesion in the left breast on contrast-enhanced CT. An ultrasoundguided core needle biopsy of the lesion was performed. Pathology showed a poorly differentiated invasive breast cancer (no special type) with lymphangiosis carcinomatosa. The tumor was strongly positive for estrogen and progesterone receptor expression and negative for Her2 with high proliferation index (Ki-67 40 %). The case was discussed within the interdisciplinary tumor board and subsequently a mastectomy with sentinel node biopsy was performed. The final TNM classification was pT2 (∅2.4 cm) pN0 (0/5, sn 0/2) cM0 L1 V0 Pn1 R0.
Therapy and course !
The patient underwent adjuvant chemotherapy with four cycles of epirubicin/cyclophosphamide (90/600 mg/m² BSA), q21 d, and 12 cycles of paclitaxel (80 mg/ m² BSA), q7 d. After completion of che-
motherapy, the patient received adjuvant radiation therapy with an overall dose of 59.4 Gy. Adjuvant antihormonal therapy with tamoxifen and leuporelinacetate was initiated. Symptoms of stiff person syndrome improved slowly but considerably and vanished completely within 4 weeks following resection. Follow-up examinations 12 months after surgery showed no recurrent disease and no neurological symptoms.
Discussion !
Completely unexplainable clinical symptoms present a challenge for the treating physician. A paraneoplastic syndrome should be considered if symptoms can’t be explained by the patient’s history, clinical examination, and laboratory and imaging tests before ending up with the diagnosis of a psychological disorder. The search for the underlying tumor of the paraneoplastic syndrome – in our case stiff person syndrome – can be strenuous or unsuccessful. If symptoms persist, cancer has to be ruled out by all diagnostic means as demonstrated in this case. In our patient mammography was negative and only targeted ultrasonography after contrast-enhanced CT revealed the tumor. If ultrasonography had also been unremarkable, magnetic resonance imaging of the breasts and PET-CT would have been indicated. The idiopathic form of stiff person syndrome is frequently caused by autoantibodies against the GABAergig synapse (Alexopoulos H et al. Eur J Clin Invest 2012; 40: 1018) and therefore can be treated effectively by diazepam/benzodiazepines (Hadavi S et al. Pract Neurol 2011; 11: 272) and plasmapheresis (Pagano MB et al. Transfusion 2014; 54: 1851). In our case the stiff person syndrome was paraneoplastic and most likely induced by autoantibodies against amphiphysin, and gephyrin. Diagnosis of paraneoplastic SPS
is proven if presented neurological symptoms vanish after cancer therapy or if cerebrospinal fluid is positive for inflammatory markers such as IgG antibodies and oligoclonal bands (Byrne TN et al. N Engl J Med. 2012; 367: 851). These are indicative and should induce testing for autoantibodies against amphiphysin, and gephyrin. Management of the primary tumor and supportive care (glucocorticoids and other immunosuppressant) provide the most promising therapeutic options (Byrne TN et al. N Engl J Med. 2012; 367: 851). Our patient is particularly young for the presentation of paraneoplastic stiff person syndrome. In a PubMed search we found three other women aged 46 (Taguchi Y et al. Rinsho Shinkeigaku 2008; 48: 410), 55 (Agarwal PA et al. Neurol India 2010; 58: 449) and 60 (Byrne TN et al. N Engl J Med. 2012; 367: 851) who were reported with secondary stiff person syndrome due to breast cancer. Potential differential diagnoses of stiff person syndrome include tetanus, multiple sclerosis and strychnine poisoning and are more or less likely depending on the particular presentation. As demonstrated by our patient, conditions in which paraneoplastic syndromes should be suspected are severe und unexplained neurological symptoms that evolve subacutely over weeks and months.
Key points !
▶ In ▶
the case of clinical symptoms, e. g. subacute onset of severe unexplainable neurological symptoms, a paraneoplastic syndrome should be considered. Breast cancer must be excluded in women by all diagnostic means if a paraneoplastic disease could be the cause for unclear clinical symptoms.
P. Dankerl, C. Rauh, D.H. Lee, R. Schulz-Wendtland, M. Uder, A. Hartmann, E. Wenkel, Erlangen, Germany
Dankerl P et al. Stiff Young Woman … Fortschr Röntgenstr 2015; 187: 589–590 · DOI http://dx.doi.org/10.1055/s-0034-1398829
Downloaded by: Universite Laval. Copyrighted material.
590
Background !
The stiff person syndrome (SPS) is a rare autoimmune neurological disorder, featuring progressive stiffness and rigidity of the axial muscles (Rakocevic G et al. Muscle Nerve 2012; 45: 623). In most cases SPS is an idiopathic disease with a suspected prevalence of approximately one per million (Ciccoto G et al. Neurol Clin. 2013; 31: 319). However, in 5 – 10 % of cases it presents as paraneoplastic disease (Alexopoulos H et al. Eur J Clin Invest 2012; 40: 1018), mostly in patients with small-cell lung carcinoma, breast carcinoma and melanoma (Pittock SJ et al. Ann Neurol 2005; 58: 96). Autoantibodies against amphiphysin, and gephyrin muscles (Rakocevic G et al. Muscle Nerve 2012; 45: 623) are strongly associated with the secondary paraneoplastic form. While idiopathic stiff person syndrome usually develops over months and features typical GAD (glutamic acid decarboxylase) antibodies (Jung YJ et al. J Mov Disord. 2014; 7: 19), the paraneoplastic version features a subacute onset (Byrne TN et al. N Engl J Med. 2012; 367: 851). Clinical presentation ranges from stiffness and spasms in the thoracoabdominal spine and proximal legs, to a change in posture and gait, worsening chronic pain and even paralysis.
Case Description !
Without a significant previous medical history, a 36-year-old Caucasian female was admitted at an outside hospital and reported to be afraid to walk without help. Initially psychological features dominated the clinical symptoms and led to the misdiagnosis of a psychogenic movement disorder. Subsequently she developed progressive muscle rigidity and stiffness of the legs and lower back paired with recurring painful spasms. This condition developed over a few weeks, and led to an inability to walk. In fact, the patient was wheelchair bound only a few weeks after initial presentation. Since the beginning of the symptoms, the patient reported that she was extremely sensitive to noise. In the clinical examination the patient presented exaggerated re-
flexes of the lower extremities and spasms as well as rigidity and stiffness of the trunk. Spasm could be also triggered by contact or noise. The gait was slow and wide to improve balance. Abnormalities of the cranial nerves were not observed. The facial and thoracic muscles were not affected.
Diagnostics !
Laboratory workup including complete blood count/white cell differentiation, electrolytes, minerals and glucose, waste products, enzymes and proteins (including C-reactive protein) was unremarkable except a 9-fold elevation of creatine kinase (1574 U/I). Tumor markers (CEA; CA 19 – 9), hormones (including thyroid stimulating hormones and antibodies) were negative. Magnetic resonance imaging (MRI) studies of the brain and the spinal cord as well as analysis of the cerebrospinal fluid revealed no abnormality. GAD (glutamic acid decarboxylase) antibodies were not detected in the cerebral spinal fluid or in the serum of the patient. Electromyography showed no reflex-myoclonus and nerve conduction velocities where nonconclusive, but both were ruled as non-diagnostic as the patient received benzodiazepine therapy at the time of testing. After treatment with diazepam at a dosage of 5 mg three times a day was initiated, symptoms improved promptly. The patient immediately underwent plasmapheresis therapy with 5 cycles. Unfortunately symptoms did not stabilize after plasmapheresis, thus treatment with diazepam had to be continued in the initial dosage. In order to protect the patient’s kidneys and clear the very high levels of creatine kinase, plasmapheresis was ordered and the patient received a Shaldon-catheter through the right internal jugular vein. Post-interventional chest Xray was normal. Following dialysis, creatine kinase normalized and continuous extensive monitoring of the patient’s laboratory values did not show relevant abnormalities. The patient’s symptoms persisted however and she received the working hypothesis of stiff person syndrome, although it was unclear whether it was idiopathic or paraneoplastic.
Contrast-enhanced whole-body computed tomography (CT) performed elsewhere in the arterial and portal venous phase was evaluated as unsuspicious. At admittance to a university breast center, the CT scan was re-evaluated and a spiculated inhomogeneous mass was identified in the left breast which was missed at initial diagno" Fig. 1). Subsequent complementary sis (● breast diagnosis including clinical examination and medio-lateral oblique digital full-field mammography of both breasts (Novation®, Siemens, Erlangen, Germany) was performed. Breast tissue density was classified as extremely dense according to ACR criteria and no suspicious lesion could " Fig. 2). Additionally ultrabe identified (● sonography (Acuson Antares®, Siemens, Erlangen, Germany) with a 14 MHz linear transducer was performed by a breast ima-
Fig. 1 Oval mass (white circle) in the left breast with higher densities than surrounding breast tissue in the contrast-enhanced CT scan.
Fig. 2 Digital full-field mammography of both breasts in mediolateral oblique projection. No suspicious lesion could be identified in the extremely dense tissue.
Dankerl P et al. Stiff Young Woman … Fortschr Röntgenstr 2015; 187: 589–590 · DOI http://dx.doi.org/10.1055/s-0034-1398829
Downloaded by: Universite Laval. Copyrighted material.
Stiff Young Woman
589
The Interesting Case
Fig. 3 Ultrasonography of the left breast with an 18 × 7 mm oval mass lesion (arrows) at 11 o’clock, 8 cm distant from the nipple. The mass lesion is isoechoic with respect to the surrounding normal fatty breast tissue (arrowhead) and to the pectoral muscle (asterix) which makes it difficult to differentiate it from normal findings.
ging expert. Sonography demonstrated an 18 × 7 mm mass lesion with an echogenicity similar to normal fatty breast tissue " Fig. 3). It was located at 11 o’clock 8 cm (● from the nipple in the left breast and matched with the mass lesion in the left breast on contrast-enhanced CT. An ultrasoundguided core needle biopsy of the lesion was performed. Pathology showed a poorly differentiated invasive breast cancer (no special type) with lymphangiosis carcinomatosa. The tumor was strongly positive for estrogen and progesterone receptor expression and negative for Her2 with high proliferation index (Ki-67 40 %). The case was discussed within the interdisciplinary tumor board and subsequently a mastectomy with sentinel node biopsy was performed. The final TNM classification was pT2 (∅2.4 cm) pN0 (0/5, sn 0/2) cM0 L1 V0 Pn1 R0.
Therapy and course !
The patient underwent adjuvant chemotherapy with four cycles of epirubicin/cyclophosphamide (90/600 mg/m² BSA), q21 d, and 12 cycles of paclitaxel (80 mg/ m² BSA), q7 d. After completion of che-
motherapy, the patient received adjuvant radiation therapy with an overall dose of 59.4 Gy. Adjuvant antihormonal therapy with tamoxifen and leuporelinacetate was initiated. Symptoms of stiff person syndrome improved slowly but considerably and vanished completely within 4 weeks following resection. Follow-up examinations 12 months after surgery showed no recurrent disease and no neurological symptoms.
Discussion !
Completely unexplainable clinical symptoms present a challenge for the treating physician. A paraneoplastic syndrome should be considered if symptoms can’t be explained by the patient’s history, clinical examination, and laboratory and imaging tests before ending up with the diagnosis of a psychological disorder. The search for the underlying tumor of the paraneoplastic syndrome – in our case stiff person syndrome – can be strenuous or unsuccessful. If symptoms persist, cancer has to be ruled out by all diagnostic means as demonstrated in this case. In our patient mammography was negative and only targeted ultrasonography after contrast-enhanced CT revealed the tumor. If ultrasonography had also been unremarkable, magnetic resonance imaging of the breasts and PET-CT would have been indicated. The idiopathic form of stiff person syndrome is frequently caused by autoantibodies against the GABAergig synapse (Alexopoulos H et al. Eur J Clin Invest 2012; 40: 1018) and therefore can be treated effectively by diazepam/benzodiazepines (Hadavi S et al. Pract Neurol 2011; 11: 272) and plasmapheresis (Pagano MB et al. Transfusion 2014; 54: 1851). In our case the stiff person syndrome was paraneoplastic and most likely induced by autoantibodies against amphiphysin, and gephyrin. Diagnosis of paraneoplastic SPS
is proven if presented neurological symptoms vanish after cancer therapy or if cerebrospinal fluid is positive for inflammatory markers such as IgG antibodies and oligoclonal bands (Byrne TN et al. N Engl J Med. 2012; 367: 851). These are indicative and should induce testing for autoantibodies against amphiphysin, and gephyrin. Management of the primary tumor and supportive care (glucocorticoids and other immunosuppressant) provide the most promising therapeutic options (Byrne TN et al. N Engl J Med. 2012; 367: 851). Our patient is particularly young for the presentation of paraneoplastic stiff person syndrome. In a PubMed search we found three other women aged 46 (Taguchi Y et al. Rinsho Shinkeigaku 2008; 48: 410), 55 (Agarwal PA et al. Neurol India 2010; 58: 449) and 60 (Byrne TN et al. N Engl J Med. 2012; 367: 851) who were reported with secondary stiff person syndrome due to breast cancer. Potential differential diagnoses of stiff person syndrome include tetanus, multiple sclerosis and strychnine poisoning and are more or less likely depending on the particular presentation. As demonstrated by our patient, conditions in which paraneoplastic syndromes should be suspected are severe und unexplained neurological symptoms that evolve subacutely over weeks and months.
Key points !
▶ In ▶
the case of clinical symptoms, e. g. subacute onset of severe unexplainable neurological symptoms, a paraneoplastic syndrome should be considered. Breast cancer must be excluded in women by all diagnostic means if a paraneoplastic disease could be the cause for unclear clinical symptoms.
P. Dankerl, C. Rauh, D.H. Lee, R. Schulz-Wendtland, M. Uder, A. Hartmann, E. Wenkel, Erlangen, Germany
Dankerl P et al. Stiff Young Woman … Fortschr Röntgenstr 2015; 187: 589–590 · DOI http://dx.doi.org/10.1055/s-0034-1398829
Downloaded by: Universite Laval. Copyrighted material.
590
