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Can white matter changes occur in disorders of peripheral nerve hyperexcitability?
Multiple Sclerosis and Related Disorders (2013) 2, 388–390
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
Can white matter changes occur in disorders of peripheral nerve hyperexcitability? Mary Sedarous⁎, Dale J. Lange Department of Neurology, Hospital for Special Surgery and Weill Cornel Medical Center, New York, NY, USA
1.
Introduction
In 1961, Isaac described an acquired syndrome of continuous muscle fiber activity originating in peripheral nerve and now known to be caused by antibodies against voltage gated potassium channels (Isaacs 1961; Sinha et al., 1991; Shillito et al., 1995). In other disorders associated with these antibodies, such as Morvan's syndrome and limbic encephalitis, patients exhibit signs of nerve hyperexcitability in the peripheral nervous system (PNS) including muscle twitching caused by myokymia or fasciculations, autonomic involvement manifested as hyperhydrosis, and in those with central nervous system disease, encephalopathy and seizures(Vincent, 2008). The clinical presentation largely depends on the permeability and binding affinity of the antibodies to different subunits of the potassium channels (Vincent, 2008). There are different types of potassium channels and many have been implicated in a number of hereditary disorders such as benign familial neonatal epilepsies (KCNQ2 and KCNQ3), peripheral nerve hyperexcitability (KCNQ2), and episodic ataxia type 1 (KCNA1) (Maljevic et al., 2010; Tomlinson et al., 2010). These disorders can also occur in the context of autoimmune conditions (Benatar, 2000). Therefore, the same disease phenotype may result from either a genetic mutation or autoimmune condition that targets the same proteins. Phenotypic variability occurs within families with some having fasciculations and cramps, and others with episodic ataxia, benign neonatal convulsions or paroxysmal dyskinesia (Falace et al., 2007; Browne
⁎
Corresponding author. Tel.: +1 718 404 6183. E-mail address: [email protected] (M. Sedarous).
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.03.008
et al., 1994; Rea et al., 2002). None have central nervous system pathology detected on neuro imaging. The wide spectrum of phenotypes may result in a diagnostic conundrum, mimicking multisystem disease. Here we describe phenotypic variation in a family with peripheral nerve hyperxcitability and seizures with one individual exhibiting signs of demyelinating disease and white matter changes on brain MRI.
2.
Patients
This three generation family originates from Germany and Switzerland (Fig. A.1). There is no consanguinity.
2.1.
Proband
A 39 year old man presented with a 3 year history of progressive muscle twitching and cramps in the calves, initially noted after exercise. The twitching spread to the left calf and other distant muscle groups and became more continuous in the calves. He had no sensory complaint or weakness. He also noted hyperhydrosis and poor memory. Examination showed markedly large calves right more than left with constant muscle twitching on the right. There was intermittent twitching in the quadriceps, hamstrings, biceps and intrinsic hand muscles as well. Electromyography showed diffuse fasciculation, most pronounced in the calves. There was no other abnormal spontaneous activity. Motor units were normal. Laboratory studies for voltage gated potassium channel (VGKC) antibodies and voltage gated calcium channel antibodies were negative. CK was repeatedly elevated (200–900;
Can white matter changes occur in disorders of peripheral nerve hyperexcitability? normal o170). All other laboratory abnormalities were normal including quantitative immunoglobulin, immunofixation electrophoresis, ganglioside antibodies (GM1), LDH, Lyme, aldolase, ESR, thyroid function tests, vitamin B12 and methylmalonic acid. One year after initial presentation he complained of positional vertigo and was evaluated by another neurologist. Brain MRI showed two T2 hyperintense, non enhancing lesions in the left frontal periventricular white matter extending into the mid body of the corpus callosum (Fig. A.2). Cerebrospinal fluid (CSF) analysis showed normal total protein, glucose, and cell count. Oligoclonal bands (OCBs) were identified in the CSF. BAER, SSEP, VER, EEG and MRI of the spinal cord were all normal. The vertigo improved, but later he had 2 additional episodes of vertigo one year apart, lasting 2–3 months. His vertigo remained characteristically positional and fatigued with time. Repeat MRIs over the course of 18 months showed no new lesions. He had no other clinical events that can support the diagnosis of multiple sclerosis (MS), however his other neurologist recommended starting disease modifying medications for MS. Mostly this was on the basis of MRI findings, the presence of OCBs in the CSF, and recurrent vertigo but the patient declined. He continues to have occasional vertigo but developed no other neurological symptoms over the course of two years.
2.2.
Other family members
Mother, sister and brother have intermittent calf twitching and cramps. Symptoms started in adulthood and were generally less in frequency and intensity than our patient. They all have hypertrophy of the calves which is viewed as a “family trait”. Electromyography performed on the brother showed fasciculation potentials in the calves but no other abnormalities. Information was not obtainable for one of the siblings. He has two daughters, age 10 and 12, both have occasional muscle cramps. A nephew is 2 years old with refractory epilepsy since infancy. He was born full term with no complications. The etiology for his epilepsy remains unclear and despite multiple medications his epilepsy remains uncontrolled.
3.
Results
Genetic analysis was performed from peripheral blood by Medical Neurogenetics Lab. Samples were tested for KCNA1 gene and no mutations were detected.
4.
Discussion
Neuromyotonia, myokymia, and fasciculation are included in the spectrum of diffuse peripheral nerve hyperexcitability (PNH). Although most commonly PNH occurs in the setting of autoimmune disease, only 40% of patients are found to have anti-VGKC antibodies in one study (Hart et al., 2002). Other clinical features of Isaac syndrome include hyperhydrosis, muscular hypertrophy and cramps, all of which are present in our patient (case II-7). One finding not previously reported is white matter changes in the brain except in cases of Morvan's syndrome where there is peripheral, autonomic, as well as CNS involvement
389
varying from hallucinations and insomnia to encephalopathy(Liguori et al., 2001; Deymeer et al., 2005). Our patient does not exhibit symptoms of CNS dysfunction except for poor memory and possibly vertigo which may be purely on peripheral basis. The MRI of the brain however demonstrates abnormal white matter signals in the corpus callosum along with OCBs in his CSF. Other neurologists felt the need to initiate treatment for MS based on these findings. However, after 2 years with no treatment for MS, there were no significant changes on MRI of the brain, and the patient did not complain of new neurological deficits. This patient highlights the importance of clinical and radiological progression and dissemination of disease in time and space to make the proper diagnosis of multiple sclerosis. The etiology of the white matter lesions is uncertain. It is possible that they represent central nervous system manifestations of an autosomal disorder whose primary clinical manifestation is peripheral nerve hyperexcitability. Although there is no direct clinical or electrophysiological evidence in our patient to suggest hyperexcitability in the CNS, our patient's nephew (case III-2) is an infant with refractory epilepsy. Similar scenarios have been described in the literature where there is phenotypic variation between members of the same family with similar mutations. In 2007, Falace et al. described a family with inherited neuromyotonia where one individual had cramps, fasciculations, and seizures, and other family members had variable degrees of cramps and fasciculations without seizures (Falace et al., 2007). Dedek et al. (2001) described a family with myokymia in the mother, and a combination of benign familial neonatal epilepsy in her twin daughters, and their half sister. They identified a mutation affecting the voltage sensor in potassium channels KCNQ2 in all affected members of this family. Conversely, the family presented by Falace was tested for mutations in KCNQ2 and KCNA1, KCNA2, and KCNA6 and none were identified. Perhaps because the mutations are in proteins associated with potassium channels and not in subunits of the channels themselves. Contactin-associated protein-like 2 (Caspr2) is expressed in the CNS and PNS and is associated with VGKC (Lancaster et al., 2011). A recent study showed that a number of patients with autoimmune encephalitis and neuromyotonia express antibodies against Caspr2 (Lancaster et al., 2011). Unfortunately testing for most of these mutations is not commercially available. We were able to test our patient for KCNA1 mutation which was negative, but given the setting and familial symptoms, it is likely due to a yet to be identified mutation in the potassium channel or the associated proteins.
Conflict of interest All authors of this case report titled “Can white matter changes occur in disorders of peripheral nerve hyperexcitability?” attest that there is no conflict of interest, and have nothing to disclose.
Appendix A See Figs. A.1 and A.2.
390
M. Sedarous, D.J. Lange 1
I
II
1
2
2
3
4
5
6
7
? III
1
2
3
4
5
Asymptomatic Fasciculation Seizures
Fig. A.1 Three generation pedigree of the family. Solid filled symbols indicate patients clinically affected by twitching. Stripe filled symbol indicates patient with seizures.
Fig. A.2 Axial and Sagital images of brain MRI–FLAIR sequence showing hyperintense white matter lesion extending into the corpus callosum.
References Benatar M. Neurological potassium channelopathies. QJM: Monthly Journal of the Association of Physicians 2000;93(12):787–97.
Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nature Genetics 1994;8 (2):136–40. Dedek K, Kunath B, Kananura C, et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proceedings of the National Academy of Sciences of the United States of America 2001;98(21):12272–7. Deymeer F, Akca S, Kocaman G, et al. fasciculations, autonomic symptoms and limbic encephalitis: a thymoma-associated Morvan's-like syndrome. European Neurology 2005;54(4):235–7. Falace A, Striano P, Manganelli F, et al. Inherited neuromyotonia: a clinical and genetic study of a family. Neuromuscular Disorders: NMD 2007;17(1):23–7. Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain: A Journal of Neurology 2002;125(Pt 8):1887–95. Isaacs HA. Syndrome of continuous muscle-fibre activity. Journal of Neurology, Neurosurgery, and Psychiatry 1961;24(4):319–25. Lancaster E, Huijbers MG, Bar V, et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Annals of Neurology 2011;69(2):303–11. Liguori R, Vincent A, Clover L, et al. Morvan’s syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain: A Journal of Neurology, 124; 2417–26. Maljevic S, Wuttke TV, Seebohm G, Lerche H. KV7 channelopathies. Pflugers Archiv: European Journal of Physiology 2010;460 (2):277–88. Rea R, Spauschus A, Eunson LH, Hanna MG, Kullmann DM. Variable K (+) channel subunit dysfunction in inherited mutations of KCNA1. The Journal of Physiology 2002;538(Pt 1):5–23. Shillito P, Molenaar PC, Vincent A, et al. Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves. Annals of Neurology 1995;38(5):714–22. Sinha S, Newsom-Davis J, Mills K, Byrne N, Lang B, Vincent A. Autoimmune aetiology for acquired neuromyotonia (Isaacs' syndrome). Lancet 1991;338(8759):75–7. Tomlinson SE, Tan SV, Kullmann DM, et al. Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1. Brain: A Journal of Neurology 2010;133(Pt 12):3530–40. Vincent A. Autoimmune channelopathies: John Newsom-Davis’s work and legacy. A summary of the Newsom–Davis Memorial Lecture 2008. Journal of Neuroimmunology 2008;201-202:245–9.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
Can white matter changes occur in disorders of peripheral nerve hyperexcitability? Mary Sedarous⁎, Dale J. Lange Department of Neurology, Hospital for Special Surgery and Weill Cornel Medical Center, New York, NY, USA
1.
Introduction
In 1961, Isaac described an acquired syndrome of continuous muscle fiber activity originating in peripheral nerve and now known to be caused by antibodies against voltage gated potassium channels (Isaacs 1961; Sinha et al., 1991; Shillito et al., 1995). In other disorders associated with these antibodies, such as Morvan's syndrome and limbic encephalitis, patients exhibit signs of nerve hyperexcitability in the peripheral nervous system (PNS) including muscle twitching caused by myokymia or fasciculations, autonomic involvement manifested as hyperhydrosis, and in those with central nervous system disease, encephalopathy and seizures(Vincent, 2008). The clinical presentation largely depends on the permeability and binding affinity of the antibodies to different subunits of the potassium channels (Vincent, 2008). There are different types of potassium channels and many have been implicated in a number of hereditary disorders such as benign familial neonatal epilepsies (KCNQ2 and KCNQ3), peripheral nerve hyperexcitability (KCNQ2), and episodic ataxia type 1 (KCNA1) (Maljevic et al., 2010; Tomlinson et al., 2010). These disorders can also occur in the context of autoimmune conditions (Benatar, 2000). Therefore, the same disease phenotype may result from either a genetic mutation or autoimmune condition that targets the same proteins. Phenotypic variability occurs within families with some having fasciculations and cramps, and others with episodic ataxia, benign neonatal convulsions or paroxysmal dyskinesia (Falace et al., 2007; Browne
⁎
Corresponding author. Tel.: +1 718 404 6183. E-mail address: [email protected] (M. Sedarous).
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.03.008
et al., 1994; Rea et al., 2002). None have central nervous system pathology detected on neuro imaging. The wide spectrum of phenotypes may result in a diagnostic conundrum, mimicking multisystem disease. Here we describe phenotypic variation in a family with peripheral nerve hyperxcitability and seizures with one individual exhibiting signs of demyelinating disease and white matter changes on brain MRI.
2.
Patients
This three generation family originates from Germany and Switzerland (Fig. A.1). There is no consanguinity.
2.1.
Proband
A 39 year old man presented with a 3 year history of progressive muscle twitching and cramps in the calves, initially noted after exercise. The twitching spread to the left calf and other distant muscle groups and became more continuous in the calves. He had no sensory complaint or weakness. He also noted hyperhydrosis and poor memory. Examination showed markedly large calves right more than left with constant muscle twitching on the right. There was intermittent twitching in the quadriceps, hamstrings, biceps and intrinsic hand muscles as well. Electromyography showed diffuse fasciculation, most pronounced in the calves. There was no other abnormal spontaneous activity. Motor units were normal. Laboratory studies for voltage gated potassium channel (VGKC) antibodies and voltage gated calcium channel antibodies were negative. CK was repeatedly elevated (200–900;
Can white matter changes occur in disorders of peripheral nerve hyperexcitability? normal o170). All other laboratory abnormalities were normal including quantitative immunoglobulin, immunofixation electrophoresis, ganglioside antibodies (GM1), LDH, Lyme, aldolase, ESR, thyroid function tests, vitamin B12 and methylmalonic acid. One year after initial presentation he complained of positional vertigo and was evaluated by another neurologist. Brain MRI showed two T2 hyperintense, non enhancing lesions in the left frontal periventricular white matter extending into the mid body of the corpus callosum (Fig. A.2). Cerebrospinal fluid (CSF) analysis showed normal total protein, glucose, and cell count. Oligoclonal bands (OCBs) were identified in the CSF. BAER, SSEP, VER, EEG and MRI of the spinal cord were all normal. The vertigo improved, but later he had 2 additional episodes of vertigo one year apart, lasting 2–3 months. His vertigo remained characteristically positional and fatigued with time. Repeat MRIs over the course of 18 months showed no new lesions. He had no other clinical events that can support the diagnosis of multiple sclerosis (MS), however his other neurologist recommended starting disease modifying medications for MS. Mostly this was on the basis of MRI findings, the presence of OCBs in the CSF, and recurrent vertigo but the patient declined. He continues to have occasional vertigo but developed no other neurological symptoms over the course of two years.
2.2.
Other family members
Mother, sister and brother have intermittent calf twitching and cramps. Symptoms started in adulthood and were generally less in frequency and intensity than our patient. They all have hypertrophy of the calves which is viewed as a “family trait”. Electromyography performed on the brother showed fasciculation potentials in the calves but no other abnormalities. Information was not obtainable for one of the siblings. He has two daughters, age 10 and 12, both have occasional muscle cramps. A nephew is 2 years old with refractory epilepsy since infancy. He was born full term with no complications. The etiology for his epilepsy remains unclear and despite multiple medications his epilepsy remains uncontrolled.
3.
Results
Genetic analysis was performed from peripheral blood by Medical Neurogenetics Lab. Samples were tested for KCNA1 gene and no mutations were detected.
4.
Discussion
Neuromyotonia, myokymia, and fasciculation are included in the spectrum of diffuse peripheral nerve hyperexcitability (PNH). Although most commonly PNH occurs in the setting of autoimmune disease, only 40% of patients are found to have anti-VGKC antibodies in one study (Hart et al., 2002). Other clinical features of Isaac syndrome include hyperhydrosis, muscular hypertrophy and cramps, all of which are present in our patient (case II-7). One finding not previously reported is white matter changes in the brain except in cases of Morvan's syndrome where there is peripheral, autonomic, as well as CNS involvement
389
varying from hallucinations and insomnia to encephalopathy(Liguori et al., 2001; Deymeer et al., 2005). Our patient does not exhibit symptoms of CNS dysfunction except for poor memory and possibly vertigo which may be purely on peripheral basis. The MRI of the brain however demonstrates abnormal white matter signals in the corpus callosum along with OCBs in his CSF. Other neurologists felt the need to initiate treatment for MS based on these findings. However, after 2 years with no treatment for MS, there were no significant changes on MRI of the brain, and the patient did not complain of new neurological deficits. This patient highlights the importance of clinical and radiological progression and dissemination of disease in time and space to make the proper diagnosis of multiple sclerosis. The etiology of the white matter lesions is uncertain. It is possible that they represent central nervous system manifestations of an autosomal disorder whose primary clinical manifestation is peripheral nerve hyperexcitability. Although there is no direct clinical or electrophysiological evidence in our patient to suggest hyperexcitability in the CNS, our patient's nephew (case III-2) is an infant with refractory epilepsy. Similar scenarios have been described in the literature where there is phenotypic variation between members of the same family with similar mutations. In 2007, Falace et al. described a family with inherited neuromyotonia where one individual had cramps, fasciculations, and seizures, and other family members had variable degrees of cramps and fasciculations without seizures (Falace et al., 2007). Dedek et al. (2001) described a family with myokymia in the mother, and a combination of benign familial neonatal epilepsy in her twin daughters, and their half sister. They identified a mutation affecting the voltage sensor in potassium channels KCNQ2 in all affected members of this family. Conversely, the family presented by Falace was tested for mutations in KCNQ2 and KCNA1, KCNA2, and KCNA6 and none were identified. Perhaps because the mutations are in proteins associated with potassium channels and not in subunits of the channels themselves. Contactin-associated protein-like 2 (Caspr2) is expressed in the CNS and PNS and is associated with VGKC (Lancaster et al., 2011). A recent study showed that a number of patients with autoimmune encephalitis and neuromyotonia express antibodies against Caspr2 (Lancaster et al., 2011). Unfortunately testing for most of these mutations is not commercially available. We were able to test our patient for KCNA1 mutation which was negative, but given the setting and familial symptoms, it is likely due to a yet to be identified mutation in the potassium channel or the associated proteins.
Conflict of interest All authors of this case report titled “Can white matter changes occur in disorders of peripheral nerve hyperexcitability?” attest that there is no conflict of interest, and have nothing to disclose.
Appendix A See Figs. A.1 and A.2.
390
M. Sedarous, D.J. Lange 1
I
II
1
2
2
3
4
5
6
7
? III
1
2
3
4
5
Asymptomatic Fasciculation Seizures
Fig. A.1 Three generation pedigree of the family. Solid filled symbols indicate patients clinically affected by twitching. Stripe filled symbol indicates patient with seizures.
Fig. A.2 Axial and Sagital images of brain MRI–FLAIR sequence showing hyperintense white matter lesion extending into the corpus callosum.
References Benatar M. Neurological potassium channelopathies. QJM: Monthly Journal of the Association of Physicians 2000;93(12):787–97.
Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nature Genetics 1994;8 (2):136–40. Dedek K, Kunath B, Kananura C, et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proceedings of the National Academy of Sciences of the United States of America 2001;98(21):12272–7. Deymeer F, Akca S, Kocaman G, et al. fasciculations, autonomic symptoms and limbic encephalitis: a thymoma-associated Morvan's-like syndrome. European Neurology 2005;54(4):235–7. Falace A, Striano P, Manganelli F, et al. Inherited neuromyotonia: a clinical and genetic study of a family. Neuromuscular Disorders: NMD 2007;17(1):23–7. Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain: A Journal of Neurology 2002;125(Pt 8):1887–95. Isaacs HA. Syndrome of continuous muscle-fibre activity. Journal of Neurology, Neurosurgery, and Psychiatry 1961;24(4):319–25. Lancaster E, Huijbers MG, Bar V, et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Annals of Neurology 2011;69(2):303–11. Liguori R, Vincent A, Clover L, et al. Morvan’s syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain: A Journal of Neurology, 124; 2417–26. Maljevic S, Wuttke TV, Seebohm G, Lerche H. KV7 channelopathies. Pflugers Archiv: European Journal of Physiology 2010;460 (2):277–88. Rea R, Spauschus A, Eunson LH, Hanna MG, Kullmann DM. Variable K (+) channel subunit dysfunction in inherited mutations of KCNA1. The Journal of Physiology 2002;538(Pt 1):5–23. Shillito P, Molenaar PC, Vincent A, et al. Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves. Annals of Neurology 1995;38(5):714–22. Sinha S, Newsom-Davis J, Mills K, Byrne N, Lang B, Vincent A. Autoimmune aetiology for acquired neuromyotonia (Isaacs' syndrome). Lancet 1991;338(8759):75–7. Tomlinson SE, Tan SV, Kullmann DM, et al. Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1. Brain: A Journal of Neurology 2010;133(Pt 12):3530–40. Vincent A. Autoimmune channelopathies: John Newsom-Davis’s work and legacy. A summary of the Newsom–Davis Memorial Lecture 2008. Journal of Neuroimmunology 2008;201-202:245–9.