CSF was studied in 23 of 28 patients. Pleocytosis was found in four patients with white blood cell count ranging from 6 to 475. Elevated CSF protein was detected in five patients with the level between 48 and 94 mg/dL. CSF glucose levels were within normal limits.
Serologic studies revealed the presence of serum VGKC antibodies using the 125I-α-dendrotoxin radioimmunoassay27 in 13 of 18 patients who were tested. Only one of five patients tested positive for CSF VGKC antibodies and this patient had positive antibodies in the blood. Acetylcholine receptor antibodies have been reported in 10 of 20 patients studied, supporting an association of Morvan syndrome with thymoma in myasthenic patients. Surprisingly, only seven of these patients exhibited clinical symptoms of myasthenia gravis (MG). Other antibodies that were detected included N-type voltage-gated calcium channel (two of four patients) and glutamic acid dexarboxylase antibodies (two of five patients). P/Q-type voltage-gated calcium channel antibodies were negative in all five patients tested.
Electrophysiological findings are summarized in Table 3. The most common abnormality seen on NCS was after-discharges, detected in 11 of 24 patients. In a minority of cases, axonal or demyelinating neuropathic features were reported. Repetitive nerve stimulation was performed in 10 patients, five of whom had clinical MG and five without any clinical findings of MG. Among those five patients with clinical MG, significant decrement of the compound muscle action potential amplitudes was reported for two patients. Two patients had normal repetitive nerve stimulation at a low rate; however, they had up to a 42% increment at 30 Hz. Repetitive nerve stimulation was normal in four of the five patients who did not have clinical MG. The fifth patient had an increment of more than 160% at slow-frequency stimulation immediately and at 1 minute after exercise. Electromyographic findings of myokymia or NMT were reported in 26 of 27 patients. Fibrillation potentials and positive sharp wave were recorded only in two patients.4,11 In one patient, profuse fasciculations were present as the sole abnormality. Other less common electromyographic abnormalities were myopathic motor unit potentials recorded in one patient. No EMG was performed on one patient who exhibited clear clinical signs of irregular muscle contractions. EEG was performed on 17 patients and was abnormal in 13; the most common abnormality was generalized slowing recorded in nine patients. Left temporal sharp waves, bitemporal sharp waves, bilateral frontotemporal slowing, and minor transitory changes that were related to drug effect; each was recorded in one of the four remaining patients. Of the five patients with seizures, only three had documented EEG results. EEG showed sharp waves in two patients and was normal in the remaining one.
Thymoma is the most common tumor associated with Morvan syndrome. It was found in 14 of 25 patients in this review; in addition, one patient was reported to have thymic follicular hyperplasia. Malignant and invasive forms were reported in five patients, including our patient; the remaining patients reportedly had benign pathology. Other tumors associated with the disease have included pulmonary adenocarcinoma,2 pulmonary hyalinizing granuloma,4 sigmoid carcinoma in situ, and prostate adenoma.16 All eight patients with Morvan syndrome and symptoms of MG, which includes double vision, ptosis, and weakness, and had thymoma or thymic hyperplasia. On the other hand, only seven of the 17 patients without MG had a thymoma.
Of the 15 patients with thymic abnormalities, only one patient did not have thymectomy; his thymoma was discovered postmortem. Of the remaining 14 patients, follow-up was documented in 12. Six of the 12 patients improved completely without recurrence, five patients had mild persistent or recurrent symptoms requiring continuous therapy with intravenous immunoglobulin/PE or prednisone, and only one patient did not improve after thymectomy. Of the two patients without follow-up, one improved completely and one had only partial response. The follow-up period of these patients ranged from 1.5 to 36 months. Treatment modalities for patients with Morvan syndrome are listed in Table 4. In five patients, no treatment was used. Two of these died, and three recovered without recurrence. Patients with tumors (thymoma or other tumors) underwent resection with the exception of two patients whose tumors were found postmortem. The most commonly used treatment has been immunosuppression with oral agents in 15 patients either alone or in combination with plasmapheresis or intravenous immunoglobulin (IVIg). Immunosuppressant medications have included prednisone, cyclophosphamide, azathioprine, or rituximab. The most commonly used immunomodulatory therapy has been plasmapheresis. Eight patients have had plasmapheresis along with immunosuppressants. Six of these patients exhibited clinical improvement, whereas the remaining four did not respond. Five patients were treated with IVIg with symptomatic improvement in two patients. One patient was reported to only a have a partial response. Five patients were treated with both immunomodulatory modalities as a result of failure of response to the initial therapy used. Of these, two were noted to respond to PE and one to IVIg, whereas the other did not have any improvement with either therapy. Symptomatic treatments with antiepileptic drugs were used alone in one patient with a milder form of disease to treat the peripheral hyperexcitability symptoms. These agents included valproate, carbamazepine, and phenytoin. Eight of 21 patients had recurrence of their symptoms, which most of the time were controlled by prednisone, IVIg or PE. Mild symptoms persisted in two patients. Death has been reported in five cases with autopsies performed in four of them. Cause of death was attributed to cardiac arrhythmia, hyperthermia, and congestive heart failure. No definite cause could be determined in one patient.
We described a case of Morvan syndrome with central and peripheral nervous system hyperexcitability associated with thymoma without detectable serum VGKC antibodies by radioimmunoassay and remarkable response to thymectomy. We provide the first review of clinical characteristics of Morvan syndrome cases reported in English literature. Based on our review, the hallmark features of this syndrome are encephalopathy with hallucinations, dysautonomia, and clinical or electrophysiological evidence of myokymia/NMT. We propose that these features are essential in making this diagnosis.
Severe insomnia and sleep disturbance, like those reported in our patient, are the most commonly reported CNS manifestation in Morvan syndrome present in 86% of patients. The insomnia of Morvan syndrome is similar to that described in delirium tremens and fatal familial insomnia. It is often severe, as it was in our patient, and is characterized by reduced or absent sleep spindles and K complexes; it is also characterized by REM sleep without atonia and absent or severely reduced slow wave sleep. This similarity has been attributed to a common dysfunction affecting the thalamus in all three conditions. As opposed to fatal familial insomnia in which degeneration of the thalamus is progressive, the dysfunction in Morvan syndrome is thought to be reversible related to the alteration caused by VGKC antibodies. Hallucinations and delusions were commonly associated positive symptoms related to the encephalopathy. Seizures are uncommon in Morvan syndrome; they can appear during the acute phase of the disease or a few months earlier.
Our patient had hyperhidrosis, labile blood pressure, and increased plasma and urinary catecholamines. Hyperhidrosis is the most common reported sign of autonomic hyperactivity. It has been reported in patients with reduced core temperature.6 This negates the hypothesis that hyperhidrosis is a response to increased heat generated by excessive muscle activity, which would cause increased core temperature. Subsequently, hyperhydrosis could be secondary to central autonomic dysfunction with lowering of the set-point temperature, but more likely it results from inappropriate excessive sweating caused by the hyperexcitability of peripheral sudomotor nerves.6 Increased plasma catecholamine levels have been reported by Ligouri and Josephs; it has been related to an increased release, probably of central origin, reflecting central sympathetic hyperactivity. So in Morvan syndrome, autonomic hyperactivity can be of central and/or peripheral origin.
Like in most previously reported cases, MRI of the brain was normal in our patient. This characteristic of the MRI scans of the brain have been thought by Josephs to be helpful in differentiating Morvan syndrome from paraneoplastic and autoimmune limbic encephalitis (LE) and fatal familial insomnia; however, abnormal brain MRI scans similar to those found in LE have been reported in more recent years; this might be the result of the advances achieved in MRI techniques. Subsequently, MRI is only helpful when it is normal in differentiating Morvan syndrome for LE. PET scans interestingly showed decreased metabolism of the limbic regions in the two patients on whom it was performed. Increased metabolism of the limbic region is frequently seen on PET scan in patients with LE.33 PET scans might be more sensitive and more helpful than MRI scans in differentiating Morvan syndrome from LE. Other studies that might be helpful in differentiating Morvan syndrome from paraneoplastic LE are CSF analysis. As opposed to paraneoplastic LE, patients with Morvan syndrome only rarely have evidence of inflammation in CSF studies.
VGKC antibodies were first reported by Shilito in 1995 in a patient with only peripheral nervous system hyperexcitability or Issac disease. He was the first to describe the radioimmunoassay technique using dentrotoxin, which is still used until now to detect voltage-gated potassium channel antibodies. These antibodies have been reported in 50% of patients with Issac disease; they also have been reported with a benign form of LE that is responsive to therapy. The clinical spectrum of VGKC antibodies is wide and range from headache to movement disorder, cognitive dysfunction, and seizures.26 In this review, serologic studies revealed the presence of serum VGKC antibodies in 72% of patients. These antibodies are thought to play a pathogenic role in Morvan syndrome. Arimura28 in 2002 reported that VGKC antibodies do not have a blocking effect; however, the antibodies increase the VGKC turnover decreasing the membrane density of these channels, which increase the resting membrane potential making it hyperexcitable. However, these antibodies are not detectable in all cases of Morvan syndrome or Isaac disease. There are different subunits in VGKC; it is possible that those patients with apparent negative serology carry antibodies to certain VGKC subunits that cannot be detected by immunoprecipitation. Immunoprecipitation is the commercially available technique described by Shillito27 in 1995; it uses dendrotoxin, which only binds and detects Kv1.1, 1.2 and 1.6 subunits. Immunohistochemistry has been proven more accurate than immunoprecipitation in detecting VGKC antibodies with a sensitivity approaching 90%.29 It was reported that sera from patients with LE bind preferentially to Kv1.1 channels and sera from patients with NMT and Morvan syndrome bind more strongly to Kv1.2 and Kv1.6.29 This difference in the affinity of the antibodies to different subunits of the VGKC might explain why patients testing positive for VGKC antibodies have different clinical presentation. However, this theory has been challenged in more recent years. During immunoprecipitation, more proteins than the VGKC subunits are precipitated. These proteins are proteins leucine-rich, glioma inactivated 1 protein (Lgi 1), contactin-associated protein-2 (Caspr-2), and contactin 2; they are in close relation to the VGKC and have a role in the clustering to VGKC.34 So patients with positive VGKC antibodies actually have antibodies to VGKC subunits and/or to any of these proteins. Some patients actually have antibodies to some of these proteins and not to the VGKC subunits. The different phenotypes of the diseases have been related to different antibodies directed toward one or the other of these proteins. Patients with Lgi 1 antibodies more commonly have LE. Because of the very limited number of patients with Morvan syndrome, it is not clear which antibodies are associated with this syndrome but Caspr-2 antibodies seem to be the likely culprit. It is likely that binding of Caspr-2 antibodies results in downregulation of Caspr2/VGKC subunits complexes on the peripheral nerve axon, leading to NMT and autonomic dysfunction in Morvan syndrome.34 Clinical and laboratory findings suggest that NMT or Isaac disease, VGKC antibody-related limbic encephalitis, and Morvan syndrome are probably a spectrum of the same disease.26 In our review, no significant difference in the clinical presentation, prognosis, or response to therapy has been appreciated between patients with and without antibodies.
Our patient showed electrodiagnostic evidence of peripheral nerve hyperexcitability as it has been reported in almost all patients with Morvan syndrome. Neuromyotonic and myokymic discharges on EMG and after-discharges on NCS are evidence of this motor hyperactivity. After-discharges have been reported frequently in congenital myasthenic syndromes, Issac disease, and organophosphate poisoning, which cause motor irritability,32 and congenital myasthenic syndromes. The results of this review underline the importance of the EMG in confirming the peripheral nerve hyperexcitability. NMT and myokymia are very important for the diagnosis but their absence does not completely exclude Morvan syndrome, especially in patients with a typical clinical picture. Fibrillation potentials and positive sharp waves are rarely seen. NCS results are nonspecific but helpful when repetitive after discharges are recorded.
The EEG in Morvan syndrome is mostly nonfocal, showing generalized slowing in most cases as it did in our patient. It is more likely to show sharp waves in patients with seizures but it can also be normal depending on the timing of the EEG. These findings are different than those reported with LE were focal abnormalities are frequently recorded.
Our patient had an invasive thymoma and a nonsecreting adrenal mass. It is unlikely that the adrenal tumor has contributed to the clinical picture or to the increased levels of catecholamines because the patient improved after treating only the thymic tumor. Thymoma has been associated with many neurologic diseases. MG is by far the most common manifestation followed by NMT. Morvan syndrome has been reported in less than 1% of patient with thymoma.19 However, thymoma is the most common tumor associated with Morvan syndrome found in 56% of patients in this review. It is possible that patients with Morvan syndrome and signs or symptoms of MG are more likely to have thymoma. Patients with malignant or invasive thymoma are not clinically different from those with a benign thymoma or those without a tumor; also, no difference in response to therapy has been appreciated between the different patients. Morvan syndrome has also been associated with Gold therapy, especially in the French literature.9,30 It is not clear whether gold neurotoxicity is a hypersensitivity reaction or a direct toxic effect. Experimental studies in hens showing dose-related neuropathy suggest a direct toxic effect.31
Our patient was partially treated with PE without any benefit; he then improved after excision of the invasive thymoma followed by chemo- and radiation therapy without requiring long-term immunosuppressants. From this review, the rate of improvement after tumor excision is not clear. In MG, improvement might be delayed for years after thymectomy; however, the response to thymectomy might be different in Morvan syndrome like it was in our patient who improved progressively within 2 months. Our review underlines the importance of a careful screening and excision of the thymoma when present.
Morvan syndrome is potentially fatal. Like many other paraneoplastic and autoimmune diseases, Morvan syndrome is responsive to IVIg, PE, and immunosuppressants; thus, a trial of these therapies in combination with antiepileptic drugs might be indicated.
The clinical features of Morvan syndrome are diverse and can mimic other diseases, like pheochromocytoma. The diagnosis of this syndrome can be made in the presence of encephalopathy with hallucinations, autonomic instability, and electrophysiologically confirmed myokymia and/or NMT. Thymic tumors are the most commonly associated neoplasms and should be suspected even in the presence of another apparent etiology.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
Morvan syndrome; neuromytonia; myokymia; voltage-gated potassium channels antibodies