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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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
Isaacs's syndrome; paraneoplastic syndrome; Voltage gated K channel antibodies