Isaacs' syndrome (also referred to as acquired neuromyotonia), first described by Isaac in 1961,1 is a rare disorder characterized by muscle twitching, stiffness, and cramps of extremity muscles. These symptoms of continuous muscle fiber activity persist in wakefulness and sleep and are not relieved with diazepam.2,3 Approximately one third of patients have delayed muscle relaxation after voluntary contraction such as handgrip or eye and jaw closure, referred to as pseudomyotonia. Patients may complain of weakness. Other symptoms reported include myokymia of the limb, trunk,4 face,5 and tongue6 muscles. In some patients, hypertrophy of muscles can occur due to continuous muscle activity.7 On occasion, myokymia may affect laryngeal muscles causing hoarseness and exertional dyspnea.8 Patients may experience excessive perspiration9 and weight loss. There have been reports of patients having neuromyotonia with encephalopathy manifesting as confusion, hallucinations, agitation, and insomnia. The triad of neuromyotonia, encephalopathy, and hyperhidrosis is referred to as Morvan syndrome.10
The syndrome is caused by dysfunction of peripheral nerve voltage-gated potassium channels (VGKCs), which could be due to genetic or acquired causes. The genetic form is associated with episodic ataxia type I and is caused by a mutation of the potassium channel gene KCNA1 on chromosome 12.11 The acquired forms have been associated with antibodies against VGKCs.12,13 The acquired form may occur with other autoimmune diseases, including myasthenia gravis,14,15 Addison disease, vitiligo,16 Hashimoto thyroiditis,17 vitamin B12 deficiency,18 celiac disease,19 rheumatoid arthritis,20 and penicillamine treatment.21
On electrophysiologic studies, nerve conduction studies in Isaacs' syndrome are usually normal but needle electromyography (EMG) of most muscles reveals continuous firing of motor unit potentials even at rest. There are also intermittent neuromyotonic discharges, which are sporadic bursts of single motor unit action potentials firing at rapid rates varying from 150 to 250 Hz, which have a tendency to start and stop abruptly, and the amplitude of the motor units typically wanes. These may occur spontaneously or be triggered by muscle contraction. In addition, there may be bursts of myokymia, which are in the form of single motor units firing at rates of 50–150 Hz. These bursts may appear as doublets, triplets, or multiplets. Fasciculations and fibrillation potentials may also be seen. These electrophysiologic abnormalities serve to confirm the diagnosis of Isaacs' syndrome.
The primary interest of this review is to highlight the relationship of Isaacs' syndrome to cancer. There have been multiple reports in the literature linking Isaacs' syndrome to various neoplasms. The pathophysiology is likely due to cross-reactivity of tumor antigens with neuronal VGKCs. We describe 3 cases that presented with clinical features of Isaacs' syndrome. The diagnosis was confirmed with electrical and laboratory testing. All cases were later diagnosed with underlying neoplasms underscoring the association of Isaacs' syndrome with neoplastic disease.
A 48-year old man developed myasthenic symptoms in October 1997, including diplopia, dysarthria, dysphagia, and generalized fatigue with weakness. He was treated with a course of plasmapheresis, steroids, and Mestinon. Imaging studies showed a mediastinal mass, which was resected. Pathology revealed a malignant thymoma for which he underwent radiation. Between 1997 and 2009, the patient had multiple exacerbations of myasthenia, some with respiratory failure requiring mechanical ventilation. At various times, his immunomodulating therapy included steroids, mycophenolate, azathioprine, and plasmapheresis.
He was first evaluated in our myasthenia gravis clinic in March 2009. At that time, he had developed a new symptom of burning dysesthesias in both feet. Medications at this time included mycophenolate 2 g/d, prednisone 20 mg/d, and Mestinon. The patient was a professional chef and did not abuse tobacco, alcohol, or illicit drugs. His family history was notable for cancer in his maternal grandfather and grandmother and history of rheumatoid arthritis in his mother and brother.
On examination, positive findings included intermittent myokymic contractions of gastrocnemius muscle. He also had mild facial diplegia, fatigable ptosis of the right eye, dysarthria, and proximal weakness of both legs.
On electrical testing, nerve conduction studies were normal. The needle portion of his study revealed frequent fasciculations and myokymic discharges in distal leg muscles. Laboratory findings included elevated VGKC antibodies with titer of 0.18 (normal < 0.02) and high acetylcholine receptor antibodies with blocking titer of 78 (normal < 25), and modulating titer 100 (normal < 20). Antistriatal antibodies were also elevated. The diagnosis of Isaacs' syndrome was based on the clinical presentation and elevated VGKC antibodies.
A magnetic resonance imaging scan of the thorax revealed a mass near the left diaphragm at the left T11 paraspinal level (Fig. 1). A whole body positron emission tomography scan showed increased metabolic activity in the paraspinous mass (Fig. 2). Fine-needle biopsy of this mass confirmed the diagnosis of metastatic malignant thymoma for which he received chemotherapy and radiation. Five months later, the patient died of acute liver failure, the etiology of which was undetermined.
A 64-year-old man presented with a 1½-year history of worsening episodic blepharospasms that were associated with yawning. He also complained of slurring of speech at the end of the day and a sense of stiffness in his face and neck muscles.
His medical history included deep vein thrombosis of the legs, hypertension, and anxiety. He was on venlafaxine, metoprolol, and warfarin at the time of his presentation. He did not have a family history of cancer or neuromuscular disorders. He was a financial advisor and led a hectic lifestyle. He drank alcohol moderately and denied use of illicit drugs. He quit smoking several years before presentation.
On examination, the patient could induce blepharospasm with forcible closure of eyelids. At times, this was followed by myokymic twitching of eyelids. There were fasciculations of proximal upper extremity muscles. There was a subtle weakness of finger abductors and wrist extensors bilaterally.
On nerve conduction studies, 2 of 4 motor nerves tested had partial conduction block with about 50% drop of amplitude. Other notable features included slowed conduction velocity with decrease of 15 to 20% of normal in certain segments, prolonged distal latency in 1 nerve, 3 of 4 nerves showing prolonged F wave latencies and absent F wave in 1 nerve. These findings were suggestive of diffuse demyelinating polyneuropathy. EMG revealed fasciculations, myokymic discharges in multiple extremity muscles, and inability to relax, suggestive of continuous motor unit activity or Isaacs' syndrome.
Relevant laboratory findings included marginal elevations of creatine kinase and sedimentation levels. Acetylcholine receptor binding antibodies were also mildly elevated with titer of 0.08 (normal < 0.02). On serum protein electrophoresis, there was an M spike in the gamma region. The immunofixation electrophoresis revealed biclonal gammopathy of IgG kappa and IgM kappa. Anti-MAG and anti-GM1 and VGKC antibodies were negative. A skeletal survey was negative. Bone marrow aspiration revealed lymphoplasmacytic lymphoma.
A 65-year-old man presented with weakness in both legs, muscle twitching, and cramping for 8–10 months. He denied sensory symptoms. His medical history was notable for old vertebral fractures at multiple levels resulting from a biking accident, degenerative joint disease, dyslipidemia, hypertension, and anxiety disorder. His medications included hydrochlorothiazide and venlafaxine. His family history was noncontributory. He did not smoke or abuse recreational drugs. He drank alcohol socially.
On examination, fasciculations were observed in a widespread distribution. No focal weakness or sensory deficits were noted. Deep tendon reflexes were hypoactive and planter responses were flexor. EMG studies revealed myokymic discharges in multiple muscles.
Laboratory testing was notable for elevated VGKC antibodies and mildly elevated creatine kinase levels. Screening for paraneoplastic antibodies was negative. Computed tomography scans of the chest, thorax, and abdomen were negative.
Based on his presentation, Isaacs' syndrome was diagnosed and treated with carbamazepine. Five years later, the patient developed pain in the right side of neck and upper shoulder and weakness and paresthesias of the right upper extremity. A magnetic resonance imaging of the cervical spine revealed spinal cord hemangioblastoma (Fig. 3).
There are a number of case reports in literature describing the association of Isaacs' syndrome to cancer. Many of these case reports have used synonyms of Isaacs syndrome, namely, continuous muscle fiber activity or acquired neuromyotonia. The syndrome has most often been linked to small cell carcinoma of the lung22,23 and thymoma.24,25 There are also reports of it being associated with Hodgkins lymphoma,26 plasmacytoma with IgM paraproteinemia,27 bladder28 and ovarian cancer29 (Table). To our knowledge, this is the first report of Isaacs' syndrome as a paraneoplastic syndrome of lymphoplasmacytic lymphoma and hemangioblastoma.
Patients with this syndrome typically present with muscle cramping, which is worsened by voluntary muscle contraction and diffuse fasciculations. At times, this presentation can be confused for evolving motor neuron disease or stiff person syndrome.32 The diagnosis is usually made on EMG, which shows a spectrum of abnormalities ranging from neuromyotonia; myokymic discharges occurring in duplets, triplets, or multiplets; diffuse fasciculations; and on occasions, fibrillation potentials. In our case series, EMG of patients had revealed myokymia and diffuse fasciculations. Neuromyotonic discharges were not seen. Guttmann et al in their editorial33 have opined that the distinction of myokymia and neuromyotonia is somewhat arbitrary with difference being the frequency of discharges. Both these forms of discharges share a common pathophysiologic basis, namely, dysfunction of VGKCs, and the two likely represent a continuum of the same disorder. For these reasons, Guttmann et al proposed that these syndromes be referred to as Isaacs' rather than neuromyotonia syndrome, and our case series lends support to this argument.
Isaacs' syndrome in patients with underlying cancer may occur concurrently with other paraneoplastic syndromes. Patients with thymoma may have Isaacs' syndrome and myasthenia gravis as was seen in one of our patients (case 1). Garcia-Merino et al23 reported 2 cases, and Perini et al had a case of Isaacs' and thymoma with concurrent peripheral neuropathy. Toepfer et al30 presented a case of small cell carcinoma having Isaacs', peripheral neuropathy, and cerebellar symptoms in association with anti-Hu antibodies. One of our patient (case 2) of Isaacs' syndrome with lymphoplasmacytic lymphoma had concurrent chronic inflammatory demyelinating polyneuropathy in association with biclonal gammopathy. Overlap of these paraneoplastic syndromes can pose diagnostic challenge particularly at the initial patient presentation.
In some of the cases of acquired Isaacs', the pathophysiology behind the hyperexcitability of peripheral nerves has been linked to autoantibodies directed against the VGKC antibodies.34,35 Hart et al36 in their series reported that 38% of patients with EMG findings of myokymia tested positive for VGKC, and in the subset of these patients with thymoma, 80% tested positive for the antibodies. In our case series, 2 patients were positive for the antibody and the test was helpful in confirming their diagnosis.
Anticovulsants, namely, carbamazepine, phenytoin, sodium valproic acid, lamotrigine, or acetazolamide are used for symptomatic relief in patients with Isaacs' syndrome and are fairly effective in controlling the muscle spasms and fasciculations. Hayat et al31 treated 3 patients, 2 of whom had metastatic thymoma, with plasma exchange with good results, suggesting that immunomodulation therapies may be of benefit. In the case reports of paraneoplastic Isaacs' syndrome, treatment directed to the underlying cancer usually improved the symptoms although there may be exceptions. In patients with thymoma, symptoms may persist despite resection of tumor possibly due to persistence of memory cells.23 In our case series, we were unable to get adequate follow-up. The patient with thymoma died of undiagnosed liver condition. Patient with lymphoplasmacytic lymphoma was treated with Rituxan, but he did poorly and died of medical complications including sepsis and thromboembolism. Case 3 underwent surgical resection of the hemangioblastoma and did well. He was successfully able to discontinue carbamazepine. He stopped coming for follow-up but, on phone interview, did report that he had not experienced any recurrence of his symptoms in the 2 years since his surgery.
Diagnosis of Isaacs' syndrome in a patient should prompt a search for underlying tumor. If search for neoplasm is negative, then periodic screening for a few years should be considered. Common cancers linked to Isaacs' syndrome include small cell carcinoma of lung and thymomas, but there are reports of hematopoetic malignancies and visceral malignancies also associated with this syndrome. We add hemangioblastoma and lymphoplasmacytic lymphoma to the known neoplasms that can be preceded by Isaacs' syndrome.
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