Journal of the Neurological Sciences 353 (2015) 175–176
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Post-therapy normalization of brain FDG-PET in Morvan's syndrome
Keywords: Neuromyotonia Encephalopathy Morvan's syndrome Voltage-gated potassium channel-complex antibodies Anti-CASPR2 antibodies Brain FDG-PET
Dear Editor, Morvan's syndrome (MoS) is a very rare disorder that manifests with overlapping symptoms involving the CNS, and peripheral nerve hyperexcitability. Historically, MoS had been associated with antibodies to the complex of voltage gated potassium channels (VGKC) [1], which have been recently classified according to subspecificities, so that contactin-associated protein-2 (CASPR-2), leucine-rich glioma inactivated-1, and contactin-2 result the three target proteins of the autoimmune response in MoS [2,3]. We describe an MoS patient, who showed non-typical EMG features, and reversible brain fluorodeoxyglucose-positron emission tomography (FDG-PET) abnormalities. A 60-year-old man presented with a 6-month history of cramps and burning pain in the lower limbs. Three months before the admission, he suffered from a five-hour lasting acute confusional state with deficits in short-term memory. Normal EEG and brain MRI led to a diagnosis of transient global amnesia. Hereafter, he had no signs of cognitive impairment. On admission, neurological examination revealed fasciculations in upper and lower limbs, and in trunk; deep tendon reflexes were brisk, and plantar responses flexor; muscle bulk and strength, and sensory systems were unaffected. Routine laboratory exams, including thyroid function tests, and autoantibodies (ANA, ENA, ANCA) were normal, except for high serum creatine phosphokinase levels (909 IU/ L; reference values, 5–145). Cerebrospinal fluid (CSF) analysis was normal, and oligoclonal IgG bands were absent. ENG showed normal motor and sensory nerve responses. EMG disclosed fasciculations in the following muscles: first dorsal interosseous, extensor digitorum communis, deltoid, tibialis anterior and gastrocnemius bilaterally. Gabapentin (1200 mg/day) was administered without benefit. After 3 months, the patient presented a partial motor seizure with secondary generalization. EEG and brain MRI were normal. Carbamazepine (600 mg/day) was the therapeutic choice. Given the coexistence of seizure, increased serum creatine phosphokinase levels, and painful cramps, the patient underwent a muscle biopsy, which showed non-specific abnormalities, and ruled out mitochondrial diseases. The patient was fairly well, when after 6 months, he began sweating profusely, and manifested sleep disturbances, mild memory impairment,
http://dx.doi.org/10.1016/j.jns.2015.03.035 0022-510X/© 2015 Elsevier B.V. All rights reserved.
and irritability. EEG and brain MRI were normal. Testing for antibodies to onconeural antigens, and to cell surface/synaptic receptors resulted positive for anti-CASPR-2 antibodies (titer 1/1280; cell-based assay, Euroimmun, Germany). EMG showed fasciculations in gastrocnemius muscles bilaterally, but not doublets/multiplets of involuntary motor unit potentials (MUPs), trains of high-frequency MUP discharges, and fibrillation potentials. Symptoms of peripheral hyperexcitability, and of the CNS and autonomic system involvement, along with seropositivity for anti-CASPR-2 antibodies led to the diagnosis of MoS. Total body CT and whole-body PET excluded the presence of tumor. Serum concentrations of commonly-tested tumor markers were within normal ranges. Performed for further investigation of patient's neuropsychiatric symptoms, brain FDG-PET scan showed hypermetabolism in the left temporal region (Fig. 1, panel A). The increase in carbamazepine dosage to 900 mg/die reduced cramps and fasciculations, and, only partially, pain. Intravenous methylprednisolone (1 g/day for 5 days), followed by oral prednisone (75 mg/day), improved pain and hyperhidrosis. However, the behavioral corticosteroid-related side effects unveiled typical features of MoS, namely disinhibition, irritability, and aggressiveness, so that the therapy was stopped after 1 month. The patient underwent 5 cycles of plasma exchange, and 5 infusions of intravenous immunoglobulins (0.4 g/Kg/day), without improvement. Azathioprine (2.5 mg/Kg/day) was then started. Six months after starting azathioprine, the patient improved, showing no cramps and sweating. Pain was continuous no more, but fluctuated over weeks. Irritability persisted unchanged. There were no fasciculations at neurological examination. Interestingly, anti-CASPR-2 antibody titer decreased (1/640), and the brain FDG-PET normalized (Fig. 1, panel B). In our case, high serum levels of anti-CASPR-2 antibodies were fundamental for the diagnosis of MoS. Indeed, both the clinical presentation, which was almost exclusively characterized by cramps and pain in the lower limbs, and the paraclinical features initially required a muscle biopsy to exclude myopathies and mitochondrial diseases. Moreover, EMG, a mainstay test for MoS, was atypical, showing the electrophysiological correlates of fasciculations only, without fibrillation potentials, myokymic and neuromyotonic discharges. Such correlates were present in 97% of the patients of the largest MoS cohort so far reported [3]. They showed clinical signs of neuromyotonia, which were absent in our patient, concordantly with the absence of neuromyotonic discharges. Brain MRI and CSF findings were normal in our patient, as expected in a disease with prevalent peripheral involvement, and as previously reported [2,4]. Conversely, brain MRI in VGKC-complex-related encephalitis shows enlargement, T2 hyperintensity, enhancement, and restricted diffusion of the mesial temporal lobes in acute phases, with progression or, occasionally, resolution after immunotherapy [5]. However, brain FDG-PET, performed away from the unique seizure, showed hypermetabolism in the left temporal lobe, which likely accounted for the neuropsychiatric symptoms, and, particularly, the memory impairment. In the largest MoS series, only 4 patients underwent
176
Letter to the Editor
Fig. 1. Brain fluorodeoxyglucose-positron emission tomography scans show hypermetabolism in the left temporal region (panel A, arrow), which normalized 6 months after immunotherapy (panel B).
brain FDG-PET, showing heterogeneous patterns that ranged from hypermetabolism to hypometablolism, either focal or generalized [3]. Their brain MRI was normal, supporting the notion that functional rather than structural damage underlies neuropsychiatric symptoms in MoS. Other MoS patients showed heterogeneous brain FDG-PET pictures: hypermetabolism in the basal ganglia [6], hypometabolism in either bilateral orbitofrontal and antero-lateral temporal regions [7], or in the left precentral and right middle temporal areas [8]. FDG-PET picture improved after immunotherapy in one case only [6]. Corticosteroids were stopped for the neuropsychiatric side effects. The patient was unresponsive to both plasma exchanges and endovenous immunoglobulins, but responded to azathioprine, which led to the reduction of serum anti-CASPR-2 antibody titer, brain FDG-PET normalization, and cessation of sweating. However, the correlation between the decreased antibody titer and the clinico-radiological improvement is untenable, as the antibody titer varied by only one dilution. In another MoS patient, who was substantially unresponsive to immunotherapies, serum anti-VGKC-complex antibody titers remained high [7]. Recently-proposed criteria for ‘neuronal surface antibodies syndrome’ recommend monitoring for tumor development for 4 years [9]. In conclusion, our case suggests that MoS diagnosis is difficult when signs and symptoms are partial, and manifest over time, without typical EMG features. Anti-CASPR-2 antibodies, which cause depolarization and muscle hyperactivity [2], are fundamental for the diagnosis. Brain FDG-PET can show abnormalities when EEG and brain MRI are normal. Conflict of interest None. References [1] Barber PA, Anderson NE, Vincent A. Morvan's syndrome associated with voltagegated K+ channel antibodies. Neurology 2000;54:771–2. [2] Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010;133:2734–48. [3] Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012;72:241–55. [4] Josephs KA, Silber MH, Fealey RD, Nippoldt TB, Auger RG, Vernino S. Neurophysiologic studies in Morvan syndrome. J Clin Neurophysiol 2004;21:440–5.
[5] Kotsenas AL, Watson RE, Pittock SJ, Britton JW, Hoye SL, Quek AM, et al. MRI findings in autoimmune voltage-gated potassium channel complex encephalitis with seizures: one potential etiology for mesial temporal sclerosis. Am J Neuroradiol 2014;35:84–9. [6] Spinazzi M, Argentiero V, Zuliani L, et al. Immunotherapy-reversed compulsive, monoaminergic, circadian rhythm disorder in Morvan syndrome. Neurology 2008; 71:2008–10. [7] Toosy AT, Burbridge SE, Pitkanen M, et al. Functional imaging correlates of frontotemporal dysfunction in Morvan's syndrome. J Neurol Neurosurg Psychiatry 2008; 79:734–5. [8] Kim NH, Vincent A, Irani SR, et al. Long-term clinical course with voltage-gated potassium channel antibody in Morvan's syndrome. J Neurol 2013;260:2407–8. [9] Zuliani L, Graus F, Giometto B, Bien C, Vincent A, et al. Central nervous system neuronal surface antibody associated syndrome: review and guidelines for recognition. J Neurol Neurosurg Psychiatry 2012;83:638–45.
L. Benedetti⁎ Department of Neurology, Osp. S. Andrea, La Spezia, Italy ⁎Corresponding author at: Department of Neurology, Osp. S. Andrea, Via Vittorio Veneto 197, 19100 La Spezia, Italy. Tel.: +39 0187 533386; fax: +39 0187 533024. E-mail address: [email protected]. D. Franciotta Laboratory of Neuroimmunology, ‘C. Mondino’ National Neurological Institute, Pavia, Italy M. Zoccarato Department of Neuroscience, University of Padova, Italy A. Beronio M. Godani E. Schirinzi Department of Neurology, Osp. S. Andrea, La Spezia, Italy G. Siciliano Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, Italy A. Ciarmiello Department of Nuclear Medicine, Osp. S. Andrea, La Spezia, Italy M. Del Sette Department of Neurology, Osp. S. Andrea, La Spezia, Italy 21 January 2015
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Post-therapy normalization of brain FDG-PET in Morvan's syndrome
Keywords: Neuromyotonia Encephalopathy Morvan's syndrome Voltage-gated potassium channel-complex antibodies Anti-CASPR2 antibodies Brain FDG-PET
Dear Editor, Morvan's syndrome (MoS) is a very rare disorder that manifests with overlapping symptoms involving the CNS, and peripheral nerve hyperexcitability. Historically, MoS had been associated with antibodies to the complex of voltage gated potassium channels (VGKC) [1], which have been recently classified according to subspecificities, so that contactin-associated protein-2 (CASPR-2), leucine-rich glioma inactivated-1, and contactin-2 result the three target proteins of the autoimmune response in MoS [2,3]. We describe an MoS patient, who showed non-typical EMG features, and reversible brain fluorodeoxyglucose-positron emission tomography (FDG-PET) abnormalities. A 60-year-old man presented with a 6-month history of cramps and burning pain in the lower limbs. Three months before the admission, he suffered from a five-hour lasting acute confusional state with deficits in short-term memory. Normal EEG and brain MRI led to a diagnosis of transient global amnesia. Hereafter, he had no signs of cognitive impairment. On admission, neurological examination revealed fasciculations in upper and lower limbs, and in trunk; deep tendon reflexes were brisk, and plantar responses flexor; muscle bulk and strength, and sensory systems were unaffected. Routine laboratory exams, including thyroid function tests, and autoantibodies (ANA, ENA, ANCA) were normal, except for high serum creatine phosphokinase levels (909 IU/ L; reference values, 5–145). Cerebrospinal fluid (CSF) analysis was normal, and oligoclonal IgG bands were absent. ENG showed normal motor and sensory nerve responses. EMG disclosed fasciculations in the following muscles: first dorsal interosseous, extensor digitorum communis, deltoid, tibialis anterior and gastrocnemius bilaterally. Gabapentin (1200 mg/day) was administered without benefit. After 3 months, the patient presented a partial motor seizure with secondary generalization. EEG and brain MRI were normal. Carbamazepine (600 mg/day) was the therapeutic choice. Given the coexistence of seizure, increased serum creatine phosphokinase levels, and painful cramps, the patient underwent a muscle biopsy, which showed non-specific abnormalities, and ruled out mitochondrial diseases. The patient was fairly well, when after 6 months, he began sweating profusely, and manifested sleep disturbances, mild memory impairment,
http://dx.doi.org/10.1016/j.jns.2015.03.035 0022-510X/© 2015 Elsevier B.V. All rights reserved.
and irritability. EEG and brain MRI were normal. Testing for antibodies to onconeural antigens, and to cell surface/synaptic receptors resulted positive for anti-CASPR-2 antibodies (titer 1/1280; cell-based assay, Euroimmun, Germany). EMG showed fasciculations in gastrocnemius muscles bilaterally, but not doublets/multiplets of involuntary motor unit potentials (MUPs), trains of high-frequency MUP discharges, and fibrillation potentials. Symptoms of peripheral hyperexcitability, and of the CNS and autonomic system involvement, along with seropositivity for anti-CASPR-2 antibodies led to the diagnosis of MoS. Total body CT and whole-body PET excluded the presence of tumor. Serum concentrations of commonly-tested tumor markers were within normal ranges. Performed for further investigation of patient's neuropsychiatric symptoms, brain FDG-PET scan showed hypermetabolism in the left temporal region (Fig. 1, panel A). The increase in carbamazepine dosage to 900 mg/die reduced cramps and fasciculations, and, only partially, pain. Intravenous methylprednisolone (1 g/day for 5 days), followed by oral prednisone (75 mg/day), improved pain and hyperhidrosis. However, the behavioral corticosteroid-related side effects unveiled typical features of MoS, namely disinhibition, irritability, and aggressiveness, so that the therapy was stopped after 1 month. The patient underwent 5 cycles of plasma exchange, and 5 infusions of intravenous immunoglobulins (0.4 g/Kg/day), without improvement. Azathioprine (2.5 mg/Kg/day) was then started. Six months after starting azathioprine, the patient improved, showing no cramps and sweating. Pain was continuous no more, but fluctuated over weeks. Irritability persisted unchanged. There were no fasciculations at neurological examination. Interestingly, anti-CASPR-2 antibody titer decreased (1/640), and the brain FDG-PET normalized (Fig. 1, panel B). In our case, high serum levels of anti-CASPR-2 antibodies were fundamental for the diagnosis of MoS. Indeed, both the clinical presentation, which was almost exclusively characterized by cramps and pain in the lower limbs, and the paraclinical features initially required a muscle biopsy to exclude myopathies and mitochondrial diseases. Moreover, EMG, a mainstay test for MoS, was atypical, showing the electrophysiological correlates of fasciculations only, without fibrillation potentials, myokymic and neuromyotonic discharges. Such correlates were present in 97% of the patients of the largest MoS cohort so far reported [3]. They showed clinical signs of neuromyotonia, which were absent in our patient, concordantly with the absence of neuromyotonic discharges. Brain MRI and CSF findings were normal in our patient, as expected in a disease with prevalent peripheral involvement, and as previously reported [2,4]. Conversely, brain MRI in VGKC-complex-related encephalitis shows enlargement, T2 hyperintensity, enhancement, and restricted diffusion of the mesial temporal lobes in acute phases, with progression or, occasionally, resolution after immunotherapy [5]. However, brain FDG-PET, performed away from the unique seizure, showed hypermetabolism in the left temporal lobe, which likely accounted for the neuropsychiatric symptoms, and, particularly, the memory impairment. In the largest MoS series, only 4 patients underwent
176
Letter to the Editor
Fig. 1. Brain fluorodeoxyglucose-positron emission tomography scans show hypermetabolism in the left temporal region (panel A, arrow), which normalized 6 months after immunotherapy (panel B).
brain FDG-PET, showing heterogeneous patterns that ranged from hypermetabolism to hypometablolism, either focal or generalized [3]. Their brain MRI was normal, supporting the notion that functional rather than structural damage underlies neuropsychiatric symptoms in MoS. Other MoS patients showed heterogeneous brain FDG-PET pictures: hypermetabolism in the basal ganglia [6], hypometabolism in either bilateral orbitofrontal and antero-lateral temporal regions [7], or in the left precentral and right middle temporal areas [8]. FDG-PET picture improved after immunotherapy in one case only [6]. Corticosteroids were stopped for the neuropsychiatric side effects. The patient was unresponsive to both plasma exchanges and endovenous immunoglobulins, but responded to azathioprine, which led to the reduction of serum anti-CASPR-2 antibody titer, brain FDG-PET normalization, and cessation of sweating. However, the correlation between the decreased antibody titer and the clinico-radiological improvement is untenable, as the antibody titer varied by only one dilution. In another MoS patient, who was substantially unresponsive to immunotherapies, serum anti-VGKC-complex antibody titers remained high [7]. Recently-proposed criteria for ‘neuronal surface antibodies syndrome’ recommend monitoring for tumor development for 4 years [9]. In conclusion, our case suggests that MoS diagnosis is difficult when signs and symptoms are partial, and manifest over time, without typical EMG features. Anti-CASPR-2 antibodies, which cause depolarization and muscle hyperactivity [2], are fundamental for the diagnosis. Brain FDG-PET can show abnormalities when EEG and brain MRI are normal. Conflict of interest None. References [1] Barber PA, Anderson NE, Vincent A. Morvan's syndrome associated with voltagegated K+ channel antibodies. Neurology 2000;54:771–2. [2] Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010;133:2734–48. [3] Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012;72:241–55. [4] Josephs KA, Silber MH, Fealey RD, Nippoldt TB, Auger RG, Vernino S. Neurophysiologic studies in Morvan syndrome. J Clin Neurophysiol 2004;21:440–5.
[5] Kotsenas AL, Watson RE, Pittock SJ, Britton JW, Hoye SL, Quek AM, et al. MRI findings in autoimmune voltage-gated potassium channel complex encephalitis with seizures: one potential etiology for mesial temporal sclerosis. Am J Neuroradiol 2014;35:84–9. [6] Spinazzi M, Argentiero V, Zuliani L, et al. Immunotherapy-reversed compulsive, monoaminergic, circadian rhythm disorder in Morvan syndrome. Neurology 2008; 71:2008–10. [7] Toosy AT, Burbridge SE, Pitkanen M, et al. Functional imaging correlates of frontotemporal dysfunction in Morvan's syndrome. J Neurol Neurosurg Psychiatry 2008; 79:734–5. [8] Kim NH, Vincent A, Irani SR, et al. Long-term clinical course with voltage-gated potassium channel antibody in Morvan's syndrome. J Neurol 2013;260:2407–8. [9] Zuliani L, Graus F, Giometto B, Bien C, Vincent A, et al. Central nervous system neuronal surface antibody associated syndrome: review and guidelines for recognition. J Neurol Neurosurg Psychiatry 2012;83:638–45.
L. Benedetti⁎ Department of Neurology, Osp. S. Andrea, La Spezia, Italy ⁎Corresponding author at: Department of Neurology, Osp. S. Andrea, Via Vittorio Veneto 197, 19100 La Spezia, Italy. Tel.: +39 0187 533386; fax: +39 0187 533024. E-mail address: [email protected]. D. Franciotta Laboratory of Neuroimmunology, ‘C. Mondino’ National Neurological Institute, Pavia, Italy M. Zoccarato Department of Neuroscience, University of Padova, Italy A. Beronio M. Godani E. Schirinzi Department of Neurology, Osp. S. Andrea, La Spezia, Italy G. Siciliano Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, Italy A. Ciarmiello Department of Nuclear Medicine, Osp. S. Andrea, La Spezia, Italy M. Del Sette Department of Neurology, Osp. S. Andrea, La Spezia, Italy 21 January 2015
