Conduction block [a significant reduction in compound muscle action potential (CMAP) amplitude after proximal compared to distal stimulation] is often found in demyelinating neuropathies,6 including inflammatory neuropathies and degenerative neuropathies, such as “liability to pressure ne~ropathy.”~ There is experimental evidence that a transient conduction block can occur in rats after ischemic lesions of peripheral nerves are induced either by ligation of arterial vessels supplying nerve or by injection of arachidonic acid into peripheral arterial vessels.’ ’,16 Conduction block has also To date, recently been described in cases with necrotizing vasc~litis.’~ however, no example of a reversible conduction block has been reported in human ischemic neuropathy. Key words: neuropathy conduction block ischemia ergotamine intoxication MUSCLE & NERVE 15~467-470 1992
REVERSIBLE CONDUCTION BLOCK IN HUMAN ISCHEMIC NEUROPATHY AFTER ERGOTAMINE ABUSE VOLKER HOMBERG, MD, KARLHEINZ REINERS, MD, and KLAUS V. TOYKA, MD
We present here electrophysiological findings in a case of ergotamine induced ischemic neuropathy presenting with transient conduction block. CASE REPORT
In August 1985, a 35-year-old woman was seen for a chief complaint of bilateral painful paraesthesiae in both legs, associated with mild distal weakness of acute onset. Her medical history included hereditary pigmental retinitis, with bilateral blindness since the age of 14. She also had a long-standing history of common migraine. Two years before admission, she had developed a focal neurological defect (mild left-sided hemiparesis), probably due to a focal migrainous attack. She had had occasional seizures in the meantime, which were controlled with valproic acid. At the time of the first electrophysiological examinations, the prescribed daily dosage of dihydroergotamine mesylate to control her headaches was 5 mg, but From the Department of Neurology, Heinrich-Heme-University of Dusseldorf, Dusseldorf, Germany Address reprint requests to Volker Homberg, MD, NTC, Neurologisches Therapiecentrum, Hohensandweg 37, D-4000 Dusseldorf 1, Germany. Dr. Toyka’s present address is Neurologische Klinlk der Universitat Wurzburg, Josef-Schneider-Str. 11, D-8700 Wurzburg, Germany. Accepted for publication August 1, 1991 CCC 0148-639x1921040467-04 $04 00 0 1992 John Wiley & Sons, Inc
Ischemic Neuropathy
she admitted to a much higher intake, including the use of many cafergot suppositories every day for several weeks, each containing 2 mg of ergotamine tartrate. On examination, both feet were cold and anemic, with a skin surface temperature of 28” to 30°C. There was moderate weakness of toe and foot extensors, whereas flexors were normal. She had impaired perception of light touch, pain, and temperature from 10 cm below the knee downward. Deep-tendon reflexes were brisk symmetrically, except for decreased ankle jerks bilaterally. The CSF exam was essentially normal. After discontinuation of the ergotamine medication, motor and sensory signs improved gradually over the following 2 months. ELECTROPHYSIOLOGICAL STUDIES
Nerve conduction studies were performed using conventional techniques. Skin temperature at the lower calf was measured, but not elevated by a heating lamp. For recording compound muscle action potentials (CMAPs), surface electrodes were attached to the extensor digitorum brevis, abductor hallucis, and thenar muscles for peroneal, tibial, and median motor nerve studies, respectively. Stimulation was performed using constant current electrical pulses (duration between 0.1 and 1.0 ms) at intensities up to 100 mA. Supramaximal stimulation of at least 150% was given at distal and
MUSCLE & NERVE
April 1992
467
R.PERO)(EAL
R.PERONEAL NERVE
NERVE
4 ClONTHS LATER
&F= dlst.
dist.
Jzmv
prox.
prox.
JKIV
Sins
-
5 rns
L
F- WAVE
-
4
JlOOPV loms
FIGURE 1. Electrophysiologic recording of peroneal nerve conduction. (Upper panel) Compound muscle action potentials recorded over the extensor digitorum brevis muscle at 5 days and 4 months after onset of symptoms (Lower panel) F-wave study, obtained with a 20 times higher amplification Note absence of F-responses and low-amplitude late potentials, with a latency up to 30 ms on day 5. Four months later 4 of 10 F-responses could be obtained Note minor background EMG activity. Recording on a Medelec Mystro electromyograph
proximal sites. F-wave studies were performed for all 3 nerves by stimulation above the ankle and wrist, and persistence of F-waves was determined for 10 trials, each separated by at least 2 seconds. Sensory nerve conduction studies were performed using antidromic stimulation of the s u r d nerve at the calf, with recording from surface electrodes on the lateral side of the foot. RESULTS
The first electrophysiological investigation, performed 5 days after onset of symptoms, showed marked conduction block at the right peroneal and posterior tibial nerves, as illustrated in Figures 1 and 2. N o F-waves could be obtained after peroneal nerve stimulation. Similar results were obtained with right tibial nerve stimulation (Table 1). Sensory neurography of the right sural nerve showed a slightly diminished nerve conduction velocity with normal amplitudes of' nerve action potentials. Electromyographic recordings with standard concentric needle electrodes, performed 12 days after the acute symptom onset, revealed no evidence of denervation in peroneal or tibial nerve innervated muscles. At least 10 insertions were performed in each muscle. Follow-up elec-
468
Ischemic Neuropathy
trophysiological investigations performed 1 week, 2 months, and 4 months later (Fig. 1, Table 1) showed a steady improvement in conduction block to almost normal values in both tibial and peroneal nerves, along with increased persistence of F-waves and slight improvement of sensory conduction velocities, which was possibly due to a concomitant increase in skin temperature. At all times, electrophysiological investigations of the median nerve were normal.
R.WST TIBIAL t€ERvE
r
diSt.
FIGURE 2. Electrophysiologic recording of tibial nerve conduction. Surface electrodes were placed over the abductor hallucis muscle. Note the reduced CMAP amplitude on proximal stimulation (100 mA, stimulus duration 1 ms).
MUSCLE & NERVE
April 1992
Table 1. Summary of executive nerve conduction and EMG studies.
Measurement unit
Day 5
Day 12
2 Months later
4 Months later
mV mV
2.65 1.05 0.40 5.0 42 011 0
3.0 1.2 0.52 4.5 42 3110
3.40 2.80 0.59 5.0 40 3/10
3.10 2.90 0.95 5.0 49 4110
15.0 3.2 0.28 7.4 40
11.7 5.8 0.61 5.8 43
ND ND ND ND ND
ND ND ND ND ND
5.0 35.0* ND
ND
4.7 36$ ND
3a5 ND
R. peroneal nerve CMAP amplitude dist. CMAP amplitude prox.* Ratio area (p/d) Distal latency NCV Persistent F-waves R. posterial tibia1 nerve CMAP amplitude dist. CMAP amplitude prox.* Ratio area (pid) Distal latency NCV R. sural nerve NAP-amplitude NCV Needle examination
ms mls mV mV ms m/s CLV m/s
No PSW/FIB
5.0
Abbreviations: ND, not determined; CMAP, compound muscle action potential; NAP. nerve action potential, NCV, conducOon velocity; PSW, positive sharp waves; FIB, fibrillation potentials. *At least 150% supramaximal stimulation (up to 100 rnA at 1.0 ms). tSkin temperature 30" to 32°C. #Skin temperature 30.6"C. %kin temperature 26.9" to 27.8"C.
DISCUSSION
The clinical presentation of distal vasoconstriction, painful paresthesia, and mild-to-moderate weakness in both lower extremities in a chronic migraine patient consuming a toxic dose of ergotamine derivative, points to an ergotamine-induced neuropathy as the most likely diagnosis. Neuropathies after chronic intake of ergotamine present either as symmetrical sensory-motor neuropathies,"' or as more focal neuropathies affecting only individual nerves.'* T h e case described by Reiss et al.13 resembles our case in terms of both clinical presentation and of the reversibility of the electrophysiological abnormalities. T h e occurrence of conduction block in the electrophysiological studies in this case, however, had not been noted before in ergotamine-induced human neuropathies, and this made it necessary to consider other possible causes. There was, however, no evidence of an inflammatory neuropathy or a mechanically induced focal demyelination such as a pressure-induced lesion. The fact that conduction block was evident in multiple lower leg nerves also made a mechanically induced demyelination unlikely. In our case, the transient conduction block was associated with a mild slowing of motor nerve conduction velocity, an increased number of F-wave failures, and a transient slight decrease in sensory-nerve conduction velocity.
Ischemic Neuropathy
While longer-lasting experimental ischemic neuropathies show axonal degeneration as the prominent f e a t ~ r e , ' this ~ ' ~ obviously did not occur in our patient. Instead, conduction block prevailed, which has been reported experimentally as a sequela of femoral artery ligation." Conduction block has been reported to occur in experimental models of ischemic neuropathy, e.g., following femoral artery ligation" or arachidonic acid injections.' Nukada and Dyck8 found secondary demyelination in nerve fibers after microsphere embolization. This is in keeping with the generally held view that conduction block is related to demyelination, as shown in studies with parallel electrophysiological and morphological investigations (see ref. 2). Similar to the findings in animal models, conduction block, in our case of an ischemic neuropathy, resolved rapidly, suggesting a functional block. It appears that conduction block may also be associated with early nerve infarction in necrotizing vasculitis." Explanations other than conduction block that might account for proximal CMAP amplitude reduction have been offered by Cornblath and Sumner,' commenting upon the cases of Ropert and Metral.15 These seem, however, not to apply to our case. First, we ensured supramaximal proximal stimulation in order to exclude a common technical artifact. Second, phase ~ancellation'~ is
MUSCLE & NERVE
April 1992
469
an unlikely cause of our observations. Cancellation effects may contribute to amplitude reduction when the number of excitable motor units is greatly reduced.'l This was obviously not the case, as the distal CMAP amplitude was not much reduced. Finally, an acute ischemic lesion of the nerve between proximal and distal stimulation sites can give rise to a low proximal CMAP initially, while
the distal CMAP remains normal for a few more days until the distal segment degenerates. As shown here, the distal CMAP did not drop further, a fact which goes against this possibility. We suggest that ergotarnine-induced ischemic neuropathy should be included in the differential diagnosis of disturbances characterized by peripheral conduction block.
REFERENCES 1. Cornblath DR, Sumner AJ: Conduction block in neuropathies with necrotizing vasculitis. Muscle Nerve 1991; 14: 185. 2. Feasby TE, Brown WF, Gilbert JL, Hahn AF: T h e pathological basis of conduction block in human neuropathy. J Neurol Neurosurg Psychiatry 1985;48:293- 244. 3. Fowler CJ, Gilliat RW: Conduction velocity and conduction block after experimental ischemic nerve injury. j Neurol Scz 1981;52:221-228. 4. Horton BT, Peters GA: Clinical manifestation of excessive use of ergotamine preparation and management of withdrawal effect; report of 52 cases. Headache 1963;2: 214. 5. Magistris MR, Roth G: Long-lasting conduction block in hereditary neuropathy with liability to pressure palsies. Neurolog 1985;35:1639- 1641. 6. McDonald WI: T h e effects of experimental demyelination on conduction in peripheral nerves: A histological and electrophysiological study. 11. Electrophysiological observations. Brazn 1963;86:501-524. 7. Merhoff GC, Porter JM: Ergot intoxication: Historical review and description of unusual clinical manifestations. Ann Surg 3974; 180:773-778. 8. Nukada H, Dyck PJ: Acute ischemia causes axonal stasis,
470
Ischemic Neuropathy
swelling, attenuation, and secondary demyelination. A m Neurol 1Y87;'22 :3 1 1- 3 18. 9. Parry GJ, Linn D: Conduction block following cxperimenral nerve infarction. Neurology 1985;35:293. 10. Parry GJ, Cornblath DK, Brown M.J: Transient conduction block following acute peripheral ischemia. Muscle Netvr 1985;8:409-412. 11. Parry GJ, Linn DJ: Transient focal conduction block tollowing experimental occlusion of the vasa nervoruni. Mucle Nerve 1986;9:345-348. 1'2. Perkin GI): Ischaemic lateral popliteal nerve palsy due to ergot intoxication. J Neurol Neurosurg Psychiatry 1974;37: 1389. IS. Reiss JE, Legarda MM, Abrams BM: Unusual case of ergot neuropathy. Am Assoc E M G Electrodiafin Abstr I979;18. 14. Rhee E K , EnglandJD, Sumner AJ: A computer simulation of conduction block: Effects produced by actual block versus interphase cancellation. A m Neurol 1990;28: 146- 156. 15. Ropert A, Metral S: Conduction block in neuropathies with necrotizing vasculitis. Muscle Nrrue 1990;13: 102- 105. 16. Sladky J.r, Greenberg J H , Brown MJ: Focal ischemia alters regional glucose metabolism in rat sciatic nerve. Neurolqgy 1985;35:293.
MUSCLE & NERVE
April 1992
REVERSIBLE CONDUCTION BLOCK IN HUMAN ISCHEMIC NEUROPATHY AFTER ERGOTAMINE ABUSE VOLKER HOMBERG, MD, KARLHEINZ REINERS, MD, and KLAUS V. TOYKA, MD
We present here electrophysiological findings in a case of ergotamine induced ischemic neuropathy presenting with transient conduction block. CASE REPORT
In August 1985, a 35-year-old woman was seen for a chief complaint of bilateral painful paraesthesiae in both legs, associated with mild distal weakness of acute onset. Her medical history included hereditary pigmental retinitis, with bilateral blindness since the age of 14. She also had a long-standing history of common migraine. Two years before admission, she had developed a focal neurological defect (mild left-sided hemiparesis), probably due to a focal migrainous attack. She had had occasional seizures in the meantime, which were controlled with valproic acid. At the time of the first electrophysiological examinations, the prescribed daily dosage of dihydroergotamine mesylate to control her headaches was 5 mg, but From the Department of Neurology, Heinrich-Heme-University of Dusseldorf, Dusseldorf, Germany Address reprint requests to Volker Homberg, MD, NTC, Neurologisches Therapiecentrum, Hohensandweg 37, D-4000 Dusseldorf 1, Germany. Dr. Toyka’s present address is Neurologische Klinlk der Universitat Wurzburg, Josef-Schneider-Str. 11, D-8700 Wurzburg, Germany. Accepted for publication August 1, 1991 CCC 0148-639x1921040467-04 $04 00 0 1992 John Wiley & Sons, Inc
Ischemic Neuropathy
she admitted to a much higher intake, including the use of many cafergot suppositories every day for several weeks, each containing 2 mg of ergotamine tartrate. On examination, both feet were cold and anemic, with a skin surface temperature of 28” to 30°C. There was moderate weakness of toe and foot extensors, whereas flexors were normal. She had impaired perception of light touch, pain, and temperature from 10 cm below the knee downward. Deep-tendon reflexes were brisk symmetrically, except for decreased ankle jerks bilaterally. The CSF exam was essentially normal. After discontinuation of the ergotamine medication, motor and sensory signs improved gradually over the following 2 months. ELECTROPHYSIOLOGICAL STUDIES
Nerve conduction studies were performed using conventional techniques. Skin temperature at the lower calf was measured, but not elevated by a heating lamp. For recording compound muscle action potentials (CMAPs), surface electrodes were attached to the extensor digitorum brevis, abductor hallucis, and thenar muscles for peroneal, tibial, and median motor nerve studies, respectively. Stimulation was performed using constant current electrical pulses (duration between 0.1 and 1.0 ms) at intensities up to 100 mA. Supramaximal stimulation of at least 150% was given at distal and
MUSCLE & NERVE
April 1992
467
R.PERO)(EAL
R.PERONEAL NERVE
NERVE
4 ClONTHS LATER
&F= dlst.
dist.
Jzmv
prox.
prox.
JKIV
Sins
-
5 rns
L
F- WAVE
-
4
JlOOPV loms
FIGURE 1. Electrophysiologic recording of peroneal nerve conduction. (Upper panel) Compound muscle action potentials recorded over the extensor digitorum brevis muscle at 5 days and 4 months after onset of symptoms (Lower panel) F-wave study, obtained with a 20 times higher amplification Note absence of F-responses and low-amplitude late potentials, with a latency up to 30 ms on day 5. Four months later 4 of 10 F-responses could be obtained Note minor background EMG activity. Recording on a Medelec Mystro electromyograph
proximal sites. F-wave studies were performed for all 3 nerves by stimulation above the ankle and wrist, and persistence of F-waves was determined for 10 trials, each separated by at least 2 seconds. Sensory nerve conduction studies were performed using antidromic stimulation of the s u r d nerve at the calf, with recording from surface electrodes on the lateral side of the foot. RESULTS
The first electrophysiological investigation, performed 5 days after onset of symptoms, showed marked conduction block at the right peroneal and posterior tibial nerves, as illustrated in Figures 1 and 2. N o F-waves could be obtained after peroneal nerve stimulation. Similar results were obtained with right tibial nerve stimulation (Table 1). Sensory neurography of the right sural nerve showed a slightly diminished nerve conduction velocity with normal amplitudes of' nerve action potentials. Electromyographic recordings with standard concentric needle electrodes, performed 12 days after the acute symptom onset, revealed no evidence of denervation in peroneal or tibial nerve innervated muscles. At least 10 insertions were performed in each muscle. Follow-up elec-
468
Ischemic Neuropathy
trophysiological investigations performed 1 week, 2 months, and 4 months later (Fig. 1, Table 1) showed a steady improvement in conduction block to almost normal values in both tibial and peroneal nerves, along with increased persistence of F-waves and slight improvement of sensory conduction velocities, which was possibly due to a concomitant increase in skin temperature. At all times, electrophysiological investigations of the median nerve were normal.
R.WST TIBIAL t€ERvE
r
diSt.
FIGURE 2. Electrophysiologic recording of tibial nerve conduction. Surface electrodes were placed over the abductor hallucis muscle. Note the reduced CMAP amplitude on proximal stimulation (100 mA, stimulus duration 1 ms).
MUSCLE & NERVE
April 1992
Table 1. Summary of executive nerve conduction and EMG studies.
Measurement unit
Day 5
Day 12
2 Months later
4 Months later
mV mV
2.65 1.05 0.40 5.0 42 011 0
3.0 1.2 0.52 4.5 42 3110
3.40 2.80 0.59 5.0 40 3/10
3.10 2.90 0.95 5.0 49 4110
15.0 3.2 0.28 7.4 40
11.7 5.8 0.61 5.8 43
ND ND ND ND ND
ND ND ND ND ND
5.0 35.0* ND
ND
4.7 36$ ND
3a5 ND
R. peroneal nerve CMAP amplitude dist. CMAP amplitude prox.* Ratio area (p/d) Distal latency NCV Persistent F-waves R. posterial tibia1 nerve CMAP amplitude dist. CMAP amplitude prox.* Ratio area (pid) Distal latency NCV R. sural nerve NAP-amplitude NCV Needle examination
ms mls mV mV ms m/s CLV m/s
No PSW/FIB
5.0
Abbreviations: ND, not determined; CMAP, compound muscle action potential; NAP. nerve action potential, NCV, conducOon velocity; PSW, positive sharp waves; FIB, fibrillation potentials. *At least 150% supramaximal stimulation (up to 100 rnA at 1.0 ms). tSkin temperature 30" to 32°C. #Skin temperature 30.6"C. %kin temperature 26.9" to 27.8"C.
DISCUSSION
The clinical presentation of distal vasoconstriction, painful paresthesia, and mild-to-moderate weakness in both lower extremities in a chronic migraine patient consuming a toxic dose of ergotamine derivative, points to an ergotamine-induced neuropathy as the most likely diagnosis. Neuropathies after chronic intake of ergotamine present either as symmetrical sensory-motor neuropathies,"' or as more focal neuropathies affecting only individual nerves.'* T h e case described by Reiss et al.13 resembles our case in terms of both clinical presentation and of the reversibility of the electrophysiological abnormalities. T h e occurrence of conduction block in the electrophysiological studies in this case, however, had not been noted before in ergotamine-induced human neuropathies, and this made it necessary to consider other possible causes. There was, however, no evidence of an inflammatory neuropathy or a mechanically induced focal demyelination such as a pressure-induced lesion. The fact that conduction block was evident in multiple lower leg nerves also made a mechanically induced demyelination unlikely. In our case, the transient conduction block was associated with a mild slowing of motor nerve conduction velocity, an increased number of F-wave failures, and a transient slight decrease in sensory-nerve conduction velocity.
Ischemic Neuropathy
While longer-lasting experimental ischemic neuropathies show axonal degeneration as the prominent f e a t ~ r e , ' this ~ ' ~ obviously did not occur in our patient. Instead, conduction block prevailed, which has been reported experimentally as a sequela of femoral artery ligation." Conduction block has been reported to occur in experimental models of ischemic neuropathy, e.g., following femoral artery ligation" or arachidonic acid injections.' Nukada and Dyck8 found secondary demyelination in nerve fibers after microsphere embolization. This is in keeping with the generally held view that conduction block is related to demyelination, as shown in studies with parallel electrophysiological and morphological investigations (see ref. 2). Similar to the findings in animal models, conduction block, in our case of an ischemic neuropathy, resolved rapidly, suggesting a functional block. It appears that conduction block may also be associated with early nerve infarction in necrotizing vasculitis." Explanations other than conduction block that might account for proximal CMAP amplitude reduction have been offered by Cornblath and Sumner,' commenting upon the cases of Ropert and Metral.15 These seem, however, not to apply to our case. First, we ensured supramaximal proximal stimulation in order to exclude a common technical artifact. Second, phase ~ancellation'~ is
MUSCLE & NERVE
April 1992
469
an unlikely cause of our observations. Cancellation effects may contribute to amplitude reduction when the number of excitable motor units is greatly reduced.'l This was obviously not the case, as the distal CMAP amplitude was not much reduced. Finally, an acute ischemic lesion of the nerve between proximal and distal stimulation sites can give rise to a low proximal CMAP initially, while
the distal CMAP remains normal for a few more days until the distal segment degenerates. As shown here, the distal CMAP did not drop further, a fact which goes against this possibility. We suggest that ergotarnine-induced ischemic neuropathy should be included in the differential diagnosis of disturbances characterized by peripheral conduction block.
REFERENCES 1. Cornblath DR, Sumner AJ: Conduction block in neuropathies with necrotizing vasculitis. Muscle Nerve 1991; 14: 185. 2. Feasby TE, Brown WF, Gilbert JL, Hahn AF: T h e pathological basis of conduction block in human neuropathy. J Neurol Neurosurg Psychiatry 1985;48:293- 244. 3. Fowler CJ, Gilliat RW: Conduction velocity and conduction block after experimental ischemic nerve injury. j Neurol Scz 1981;52:221-228. 4. Horton BT, Peters GA: Clinical manifestation of excessive use of ergotamine preparation and management of withdrawal effect; report of 52 cases. Headache 1963;2: 214. 5. Magistris MR, Roth G: Long-lasting conduction block in hereditary neuropathy with liability to pressure palsies. Neurolog 1985;35:1639- 1641. 6. McDonald WI: T h e effects of experimental demyelination on conduction in peripheral nerves: A histological and electrophysiological study. 11. Electrophysiological observations. Brazn 1963;86:501-524. 7. Merhoff GC, Porter JM: Ergot intoxication: Historical review and description of unusual clinical manifestations. Ann Surg 3974; 180:773-778. 8. Nukada H, Dyck PJ: Acute ischemia causes axonal stasis,
470
Ischemic Neuropathy
swelling, attenuation, and secondary demyelination. A m Neurol 1Y87;'22 :3 1 1- 3 18. 9. Parry GJ, Linn D: Conduction block following cxperimenral nerve infarction. Neurology 1985;35:293. 10. Parry GJ, Cornblath DK, Brown M.J: Transient conduction block following acute peripheral ischemia. Muscle Netvr 1985;8:409-412. 11. Parry GJ, Linn DJ: Transient focal conduction block tollowing experimental occlusion of the vasa nervoruni. Mucle Nerve 1986;9:345-348. 1'2. Perkin GI): Ischaemic lateral popliteal nerve palsy due to ergot intoxication. J Neurol Neurosurg Psychiatry 1974;37: 1389. IS. Reiss JE, Legarda MM, Abrams BM: Unusual case of ergot neuropathy. Am Assoc E M G Electrodiafin Abstr I979;18. 14. Rhee E K , EnglandJD, Sumner AJ: A computer simulation of conduction block: Effects produced by actual block versus interphase cancellation. A m Neurol 1990;28: 146- 156. 15. Ropert A, Metral S: Conduction block in neuropathies with necrotizing vasculitis. Muscle Nrrue 1990;13: 102- 105. 16. Sladky J.r, Greenberg J H , Brown MJ: Focal ischemia alters regional glucose metabolism in rat sciatic nerve. Neurolqgy 1985;35:293.
MUSCLE & NERVE
April 1992
