European Journal of Neurology 2014, 21: e5–e6
doi:10.1111/ene.12295
LETTER TO THE EDITOR
Paraneoplastic motor neuron disease associated with breast cancer R. Spataro and V. La Bella Department of Biomedicine and Clinical Neurosciences, ALS Clinical Research Center, University of Palermo, Palermo, Italy Correspondence: V. La Bella, Department of Biomedicine and Clinical Neurosciences, ALS Clinical Research Center, University of Palermo, via G La loggia 1, 90129 Palermo, Italy (tel./fax: 0039 091 6555158; e-mail: [email protected]).
Keywords: ALSFRS-R, breast cancer, clinical progression, motor neuron disease Received: 31 July 2013 Accepted: 23 September 2013
Sir, Motor neuron diseases (MNDs) include a group of neurodegenerative disorders, affecting upper and/or lower motor neurons, whose pathogenesis is still imperfectly known [1–3]. MNDs may rarely be associated with neoplastic disorders [4,5] and in particular with breast cancer [6–8]. The relationship between MND and cancer, however, is far from being defined [9]. Here we report on a patient with a progressive upper motor neuron predominant MND who showed a marked and sustained clinical improvement after surgical excision of a breast cancer, discovered several months after the onset of the neurological symptoms. The patient is a 60-year-old housewife referred to our ALS Center in April 2010 with a 6-month history of progressive gait disorder and dysarthria. She had been previously healthy, with a family history negative for neuromuscular disorders. The neurological examination documented a spastic tetraparesis, more severe in the lower limbs, where there was a bilateral ankle clonus, toe extension and a marked rigidity. There was neither overt muscle atrophy nor fasciculations. Gait was highly spastic, impossible without a cane. Speech was dysarthric and swallowing slightly impaired. Bladder and bowel functions were reported as normal. Sensory function and coordination were normal.
© 2013 The Author(s) European Journal of Neurology © 2013 EFNS
An extensive biochemical, immunological and hormonal work-up including serum creatine phosphokinase level and antibodies anti-Hu, anti-Ri and anti-Yo were negative. A cerebrospinal fluid analysis was negative, with absent oligoclonal bands. Post-contrast brain and spine magnetic resonance imaging demonstrated only a mild cortical atrophy (no significant hyperintensities in the white matter were detected) and several disk protrusions between C4 and C7, with a normal signal intensity in the spinal cord. Asymptomatic right lateral and paramedian disk protrusions were documented at L4 L5 and L5 S1, respectively. Concentric needle electromyography showed increased and polyphasic motor unit potentials (MUPs) in the right peroneus longus (PL) and left tibialis anterior (TA). Fibrillation potentials were inconstantly detected in the left deltoideus and TA. Sensory and motor nerve conduction studies were normal in both upper and lower limbs. Motor evoked potentials in the upper (abductor digiti minimi) and lower limbs (TA) showed increased latency and decreased amplitude. Sensory evoked potentials were within normal range. The clinical presentation and progression, along with the intensive work-up, allowed a clinical diagnosis of MND, upper motor neuron predominant. Functional disability, scored with the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) [10], was 32/48 at diagnosis, with a ΔFS
[11] of 2.66, indicating a rapidly progressing disease. The seated forced vital capacity (FVC) was 94% of predicted. The patient started riluzole and was scheduled for follow-up visits. In September 2010 her neurological conditions had worsened (she walked only with a double cane), with an ALSFRS-R score of 28/48. However, in the same period, a routine general check-up led to the serendipitous discovery of a ductal breast cancer with sentinel axillary lymph nodes. She underwent a partial mastectomy and then radiotherapy followed by chemotherapy with anastrozole and docetaxel. Within 2 months after surgery, the patient noticed an improvement of the neurological symptoms. In April 2011 she could return to walk without assistance; her speech and swallowing markedly improved; the ALSFRS-R scored at 40/48. In the coming months we performed serial follow-up visits and prescribed further biochemical and neurophysiological studies. A neurological examination made in September 2011 showed an autonomous slightly rigid gait. Deep reflexes were brisk in the four limbs, with reflex extension, and no clones were found. The spastic rigidity in the lower limbs was markedly reduced. FVC was 105% of predicted. No muscle atrophy was detected. Figure 1 shows the progressive improvement of the ALSFRS-R score over the follow-up. The most recent clinical evaluation was made in May 2013 and documented a rather stable clinical
Figure 1 Profile of the ALSFRS-R total score in the MND patient. Black circles indicate visits. The ALSFRS-R score at onset is assumed to be normal [11]. The diamond symbol indicates the time of the breast cancer discovery and surgery.
e5
e6
Letter to the Editor
condition, with an ALSFRS-R score of 40/48. A repeat electromyogram made in July 2013 showed a stable neurophysiological pattern, with polyphasic MUPs in left TA and in PL bilaterally. The patient is still taking anastrozole and no signs of cancer relapse/metastasis have been documented so far. A clinical hallmark of MND is its relentless progression, irrespective of the clinical form. Typical amyotrophic lateral sclerosis progresses more rapidly than the upper motor neuron predominant MND or primary lateral sclerosis. In our patient, the DFS of 2.66 pointed to a rather aggressive MND. The disease’s clinical progression, characterized almost exclusively by upper motor neuron signs and symptoms, unexpectedly reverted when a breast cancer was discovered and excised. After the 2-year follow-up the patient is quite stable, although recovery is not complete. Motor neuron diseases have been linked to systemic cancer. A few studies have shown an association between upper motor neuron predominant MND and breast cancer, suggesting that the neurological disorder may be paraneoplastic [6,8]. However, a clinical improvement in patients with MND and breast cancer has not been documented [6–8], except for a single case with lower motor neuron syndrome which improved after tumor excision [12]. Alternatively, the chemotherapy itself (i.e. docetaxel and anastrozole) might be able to affect the disease progression. In this regard, tamoxifen, a chemotherapic agent, has already been shown to be a promising drug in amyotrophic lateral sclerosis and is now being tested in a clinical trial [13]. The patient stopped docetaxel after a few months and continued to take anastrozole. This drug crosses the blood brain barrier [14], but there are no reported effects on motor neurons. Anastrozole is an aromatase inhibitor and thus, by inhibiting estrogens, it should theoretically be harmful to motor neurons [15]. This was not the case in
our patient, who showed a sustained improvement of MND despite the continuous therapy with anastrozole. The complex relationship between ovarian hormones and breast cancer has recently been highlighted by the evidence that progesterone can promote the tumor growth [16]. This hormone seems to have a protective effect on motoneurons, and its levels correlate with a more benign course of MND [17,18]. Therefore, whether progesterone represents a biological link between breast cancer and MND is an open issue that deserves further studies. In conclusion, we have shown an MND that improved after treating a breast cancer. The reverted clinical progression after tumor excision strongly suggests that this case might be a rare paraneoplastic MND [6]. This reinforces the usefulness of a careful search for an occult breast cancer in women with upper motor neuron predominant MND [6,8]. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest. References 1. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet 2011; 377: 942–955. 2. Gordon PH, Cheng B, Katz IB, et al. The natural history of primary lateral sclerosis. Neurology 2006; 66: 647–653. 3. Van Den Berg-Vos RM, Visser J, Franssen H, et al. Sporadic lower motor neuron disease with adult onset: classification of subtypes. Brain 2003; 126: 1036–1047. 4. Rowland LP, Schneck SA. Neuromuscular disorders associated with malignant neoplastic disorders. J Chronic Dis 1963; 16: 777–795. 5. Freedman DM, Travis LB, Gridley G, et al. Amyotrophic lateral sclerosis mortality in 1.9 million US cancer survivors. Neuroepidemiology 2005; 25: 176–180. 6. Forsyth PA, Dalmau J, Graus F, et al. Motor neuron syndromes in cancer patients. Ann Neurol 1997; 41: 722–730.
7. Kijima Y, Yoshinaka H, Higuchi I, et al. A case of amyotrophic lateral sclerosis and breast cancer. Breast Cancer 2005; 12: 57–59. 8. Sadot E, Carluer L, Corcia P, et al. Breast cancer and motor neuron disease: clinical study of seven cases. Amyotroph Lateral Scler 2007; 8: 288–291. 9. Freedman DM, Curtis RE, Daugherty SE, et al. The association between cancer and amyotrophic lateral sclerosis. Cancer Causes Control 2013; 24: 55–60. 10. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci 1999; 169: 13–21. 11. Kimura F, Fujimura C, Ishida S, et al. Progression rate of ALSFRS-R at the time of diagnosis predicts survival time in ALS. Neurology 2006; 66: 265–267. 12. Ferracci F, Fassetta G, Butler MH, et al. A novel antineuronal antibody in a motor neuron syndrome associated with breast cancer. Neurology 1999; 53: 852–855. 13. Atassi N, Jackson K, Mahoney K, et al. Phase 2 selection trial of high dosage creatine and two dosages of tamoxifen in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2011; 12(Suppl. 1): SW217. 14. Miyajima M, Kusuhara H, Takahashi K, et al. Investigation of the effect of active efflux at the blood brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system. J Pharm Sci 2013; 102: 3309–3319. 15. Blasco H, Guennoc A-M, Veyrat-Durebex C, et al. Amyotrophic lateral sclerosis: a hormonal condition? Amyotroph Lateral Scler 2012; 13: 585–588. 16. Brisken C. Progesterone signaling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer 2013; 13: 385–396. 17. Kim J, Kim T-Y, Cho K-S, Kim HN, Koh J-Y. Autophagy activation and neuroprotection by progesterone in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2013; 59: 80–85. 18. Gargiulo Monachelli G, Meyer M, Rodriguez GE, et al. Endogenous progesterone is associated to amyotrophic lateral sclerosis. Acta Neurol Scand 2011; 123: 60–67.
© 2013 The Author(s) European Journal of Neurology © 2013 EFNS
doi:10.1111/ene.12295
LETTER TO THE EDITOR
Paraneoplastic motor neuron disease associated with breast cancer R. Spataro and V. La Bella Department of Biomedicine and Clinical Neurosciences, ALS Clinical Research Center, University of Palermo, Palermo, Italy Correspondence: V. La Bella, Department of Biomedicine and Clinical Neurosciences, ALS Clinical Research Center, University of Palermo, via G La loggia 1, 90129 Palermo, Italy (tel./fax: 0039 091 6555158; e-mail: [email protected]).
Keywords: ALSFRS-R, breast cancer, clinical progression, motor neuron disease Received: 31 July 2013 Accepted: 23 September 2013
Sir, Motor neuron diseases (MNDs) include a group of neurodegenerative disorders, affecting upper and/or lower motor neurons, whose pathogenesis is still imperfectly known [1–3]. MNDs may rarely be associated with neoplastic disorders [4,5] and in particular with breast cancer [6–8]. The relationship between MND and cancer, however, is far from being defined [9]. Here we report on a patient with a progressive upper motor neuron predominant MND who showed a marked and sustained clinical improvement after surgical excision of a breast cancer, discovered several months after the onset of the neurological symptoms. The patient is a 60-year-old housewife referred to our ALS Center in April 2010 with a 6-month history of progressive gait disorder and dysarthria. She had been previously healthy, with a family history negative for neuromuscular disorders. The neurological examination documented a spastic tetraparesis, more severe in the lower limbs, where there was a bilateral ankle clonus, toe extension and a marked rigidity. There was neither overt muscle atrophy nor fasciculations. Gait was highly spastic, impossible without a cane. Speech was dysarthric and swallowing slightly impaired. Bladder and bowel functions were reported as normal. Sensory function and coordination were normal.
© 2013 The Author(s) European Journal of Neurology © 2013 EFNS
An extensive biochemical, immunological and hormonal work-up including serum creatine phosphokinase level and antibodies anti-Hu, anti-Ri and anti-Yo were negative. A cerebrospinal fluid analysis was negative, with absent oligoclonal bands. Post-contrast brain and spine magnetic resonance imaging demonstrated only a mild cortical atrophy (no significant hyperintensities in the white matter were detected) and several disk protrusions between C4 and C7, with a normal signal intensity in the spinal cord. Asymptomatic right lateral and paramedian disk protrusions were documented at L4 L5 and L5 S1, respectively. Concentric needle electromyography showed increased and polyphasic motor unit potentials (MUPs) in the right peroneus longus (PL) and left tibialis anterior (TA). Fibrillation potentials were inconstantly detected in the left deltoideus and TA. Sensory and motor nerve conduction studies were normal in both upper and lower limbs. Motor evoked potentials in the upper (abductor digiti minimi) and lower limbs (TA) showed increased latency and decreased amplitude. Sensory evoked potentials were within normal range. The clinical presentation and progression, along with the intensive work-up, allowed a clinical diagnosis of MND, upper motor neuron predominant. Functional disability, scored with the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) [10], was 32/48 at diagnosis, with a ΔFS
[11] of 2.66, indicating a rapidly progressing disease. The seated forced vital capacity (FVC) was 94% of predicted. The patient started riluzole and was scheduled for follow-up visits. In September 2010 her neurological conditions had worsened (she walked only with a double cane), with an ALSFRS-R score of 28/48. However, in the same period, a routine general check-up led to the serendipitous discovery of a ductal breast cancer with sentinel axillary lymph nodes. She underwent a partial mastectomy and then radiotherapy followed by chemotherapy with anastrozole and docetaxel. Within 2 months after surgery, the patient noticed an improvement of the neurological symptoms. In April 2011 she could return to walk without assistance; her speech and swallowing markedly improved; the ALSFRS-R scored at 40/48. In the coming months we performed serial follow-up visits and prescribed further biochemical and neurophysiological studies. A neurological examination made in September 2011 showed an autonomous slightly rigid gait. Deep reflexes were brisk in the four limbs, with reflex extension, and no clones were found. The spastic rigidity in the lower limbs was markedly reduced. FVC was 105% of predicted. No muscle atrophy was detected. Figure 1 shows the progressive improvement of the ALSFRS-R score over the follow-up. The most recent clinical evaluation was made in May 2013 and documented a rather stable clinical
Figure 1 Profile of the ALSFRS-R total score in the MND patient. Black circles indicate visits. The ALSFRS-R score at onset is assumed to be normal [11]. The diamond symbol indicates the time of the breast cancer discovery and surgery.
e5
e6
Letter to the Editor
condition, with an ALSFRS-R score of 40/48. A repeat electromyogram made in July 2013 showed a stable neurophysiological pattern, with polyphasic MUPs in left TA and in PL bilaterally. The patient is still taking anastrozole and no signs of cancer relapse/metastasis have been documented so far. A clinical hallmark of MND is its relentless progression, irrespective of the clinical form. Typical amyotrophic lateral sclerosis progresses more rapidly than the upper motor neuron predominant MND or primary lateral sclerosis. In our patient, the DFS of 2.66 pointed to a rather aggressive MND. The disease’s clinical progression, characterized almost exclusively by upper motor neuron signs and symptoms, unexpectedly reverted when a breast cancer was discovered and excised. After the 2-year follow-up the patient is quite stable, although recovery is not complete. Motor neuron diseases have been linked to systemic cancer. A few studies have shown an association between upper motor neuron predominant MND and breast cancer, suggesting that the neurological disorder may be paraneoplastic [6,8]. However, a clinical improvement in patients with MND and breast cancer has not been documented [6–8], except for a single case with lower motor neuron syndrome which improved after tumor excision [12]. Alternatively, the chemotherapy itself (i.e. docetaxel and anastrozole) might be able to affect the disease progression. In this regard, tamoxifen, a chemotherapic agent, has already been shown to be a promising drug in amyotrophic lateral sclerosis and is now being tested in a clinical trial [13]. The patient stopped docetaxel after a few months and continued to take anastrozole. This drug crosses the blood brain barrier [14], but there are no reported effects on motor neurons. Anastrozole is an aromatase inhibitor and thus, by inhibiting estrogens, it should theoretically be harmful to motor neurons [15]. This was not the case in
our patient, who showed a sustained improvement of MND despite the continuous therapy with anastrozole. The complex relationship between ovarian hormones and breast cancer has recently been highlighted by the evidence that progesterone can promote the tumor growth [16]. This hormone seems to have a protective effect on motoneurons, and its levels correlate with a more benign course of MND [17,18]. Therefore, whether progesterone represents a biological link between breast cancer and MND is an open issue that deserves further studies. In conclusion, we have shown an MND that improved after treating a breast cancer. The reverted clinical progression after tumor excision strongly suggests that this case might be a rare paraneoplastic MND [6]. This reinforces the usefulness of a careful search for an occult breast cancer in women with upper motor neuron predominant MND [6,8]. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest. References 1. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet 2011; 377: 942–955. 2. Gordon PH, Cheng B, Katz IB, et al. The natural history of primary lateral sclerosis. Neurology 2006; 66: 647–653. 3. Van Den Berg-Vos RM, Visser J, Franssen H, et al. Sporadic lower motor neuron disease with adult onset: classification of subtypes. Brain 2003; 126: 1036–1047. 4. Rowland LP, Schneck SA. Neuromuscular disorders associated with malignant neoplastic disorders. J Chronic Dis 1963; 16: 777–795. 5. Freedman DM, Travis LB, Gridley G, et al. Amyotrophic lateral sclerosis mortality in 1.9 million US cancer survivors. Neuroepidemiology 2005; 25: 176–180. 6. Forsyth PA, Dalmau J, Graus F, et al. Motor neuron syndromes in cancer patients. Ann Neurol 1997; 41: 722–730.
7. Kijima Y, Yoshinaka H, Higuchi I, et al. A case of amyotrophic lateral sclerosis and breast cancer. Breast Cancer 2005; 12: 57–59. 8. Sadot E, Carluer L, Corcia P, et al. Breast cancer and motor neuron disease: clinical study of seven cases. Amyotroph Lateral Scler 2007; 8: 288–291. 9. Freedman DM, Curtis RE, Daugherty SE, et al. The association between cancer and amyotrophic lateral sclerosis. Cancer Causes Control 2013; 24: 55–60. 10. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci 1999; 169: 13–21. 11. Kimura F, Fujimura C, Ishida S, et al. Progression rate of ALSFRS-R at the time of diagnosis predicts survival time in ALS. Neurology 2006; 66: 265–267. 12. Ferracci F, Fassetta G, Butler MH, et al. A novel antineuronal antibody in a motor neuron syndrome associated with breast cancer. Neurology 1999; 53: 852–855. 13. Atassi N, Jackson K, Mahoney K, et al. Phase 2 selection trial of high dosage creatine and two dosages of tamoxifen in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2011; 12(Suppl. 1): SW217. 14. Miyajima M, Kusuhara H, Takahashi K, et al. Investigation of the effect of active efflux at the blood brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system. J Pharm Sci 2013; 102: 3309–3319. 15. Blasco H, Guennoc A-M, Veyrat-Durebex C, et al. Amyotrophic lateral sclerosis: a hormonal condition? Amyotroph Lateral Scler 2012; 13: 585–588. 16. Brisken C. Progesterone signaling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer 2013; 13: 385–396. 17. Kim J, Kim T-Y, Cho K-S, Kim HN, Koh J-Y. Autophagy activation and neuroprotection by progesterone in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2013; 59: 80–85. 18. Gargiulo Monachelli G, Meyer M, Rodriguez GE, et al. Endogenous progesterone is associated to amyotrophic lateral sclerosis. Acta Neurol Scand 2011; 123: 60–67.
© 2013 The Author(s) European Journal of Neurology © 2013 EFNS
