Brain (1975) 98, 189-202
PAROXYSMAL ATTACKS IN MULTIPLE SCLEROSIS BY
(From the Department of Neurology, University Hospital, Uppsala)
INTRODUCTION
THE occurrence of paroxysmal attacks during the course of multiple sclerosis (MS) is now well known (McAlpine, 1972). Most reports have dealt with the so-called tonic seizures. Although there were some early reports on tonic seizures in cases of probable multiple sclerosis (Determann, 1892; Guillain et al, 1928; Redlich, 1929; Decourt, 1938; Storring, 1940; Arnould et al., 1958) it was Matthews in 1958 who established the firm connexion between this particular form of attacks and MS. In 1959 Andermann et al. described paroxysmal dysarthria and ataxia which is probably one of the commonest types orpafoxysmal attacks in MS. Earner descriptions of similar or identical attacks were given by Storring (1940, Case 7) and by Parker (1946) who used the name periodic ataxia. Less common types of attacks are paroxysmal akinesia (Zeldowicz, 1961) and paroxysmal paraesthesiae and paroxysmal pain in limbs (Espir and Millac, 1970). We have previously reported an unusual type of attack, focal sensorimotor seizures of spinal origin (Ekbom et al., 1968). In that paper we proposed the hypothesis that the attacks were caused by a transversely spreading activation of damaged axons in fibre tracts of the spinal cord. Further clinical studies of MS patients exhibiting paroxysmal attaclcs of different kinds have led us to believe that this pathogenic mechanism might be operative in several other types of attacks in MS. In this paper we wish to report our collected experience of paroxysmal attacks in MS. Some types of attack have not been previously described. The different paroxysmal phenomena will be discussed in the light of our proposed hypothesis of the pathogenic mechanism. MATERIAL AND METHODS
Twenty-two patients, 14 women and 8 men, with paroxysmal attacks, were studied (Table I). They were collected from a total of 235 patients with undoubted or suspected MS, treated at the Neurological Clinic, Uppsala, during the eight-year period, 1966-1973. 14
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TABLE L—TYPES OF PAROXYSMAL SEIZURES IN 22 CASES WITH MULTIPLE SCLEROSIS, THE ATTACKS ARE DENOMINATED BY THEIR MAIN SYMPTOM
Type
No. of patients
. ^ Tonic seizures
5
Spinal sensorimotor seizures
1
Paroxysmal akinesia
1
y,' Paroxysmal dysarthria and ataxia Paroxysmal hemiataxia and crossed panesthesiae
7* 2 3
Paroxysmal numbness
2*
Paroxysmal pain
1
Paroxysmal itching ' 1 •One patient (Case 3) had during one period paroxysmal dysarthria and ataxia and during another period paroxysmal numbness.
Thus, about 9 per cent of our patients had paroxysmal symptoms during the course of their disease. This figure should be regarded only as an approximation. For instance, outpatients were not included in the study, and biasing selection factors may have been operative. The patients with paroxysmal symptoms were interviewed and examined by one or other of us. RESULTS AND CASE REPORTS
Tonic Seizures The study of tonic seizures in MS by Matthews (1958) was followed by several reports of similar cases (Joynt and Green, 1962; Kreindler et ah, 1962; Kuroiwa and Araki, 1963; Lance, 1963; Fabri and Millefiorini, 1965; Kuroiwa and Shibasaki, 1938; Castaigne et ai, 1970; Espir and Millac, 1970; Shibasaki and Kuroiwa, 1974). The attacks of tonic seizures that we observed in our patients were similar to those previously reported. As can be seen from the table, tonic seizures were the second most common type of attacks (5 patients). In no case were the attacks the initial symptom of the disease. The seizures were painful in one case. This patient also experienced paraesthesiae in the right arm and leg immediately preceding the tonic contraction. The tendon reflexes were exaggerated in the right arm in this patient. Two other patients had signs of bilateral disorder of the pyramidal tracts. In 2 cases examination during the period of attacks did not reveal anything pathological. The occurrence of the attacks varied in different patients from four to five attacks during three years, up to thirty attacks a day for one month. Spinal Sensorimotor Seizures In 1968 we reported 2 cases of spinal sensorimotor seizures (Ekbom et al., 1968). We have been unable to find any case reports of patients whose symptoms and signs corresponded exactly to those observed in our patients but similar seizures have been observed by Schnabl (1897 and 1898), Oppenheim (1899), Spiller (1927),
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Paroxysmal diplopia
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Paroxysmal Akinesia Although Zeldowicz in 1961 could report as many as 12 cases of paroxysmal akinesia or sudden loss of tone, there seems to have been only one subsequent report, in which 3 similar cases were described (Castaigne et al., 1970). We now report one more case. Case 2.—A man, aged 45, had had during three years preceding the period with the attacks, a bout of transient weakness and numbness in the legs, a bout of numbness in the left arm, and Lhermitte's sign. The diagnosis of MS was strengthened by the result of agar-gel eJectrophoresis of the cerebrospinal fluid. The attacks consisted of a sudden sensation of the right knee being "locked." He lost the tone of the muscles of the right leg, which made him stop for a few seconds. The maxima] recurrence of attacks was thirty times a day, and they ceased after about six months. With carbamazepine (TegretolR) 200 mg x 3, the frequency was reduced to 1/3. Unfortunately, an allergic skin reaction developed after fourteen days, which made further treatment impossible. Paroxysmal Dysarthria and Ataxia Several previous reports have dealt with paroxysmal dysarthria and ataxia (Andermann et al, 1959; Lugaresi et al, 1962; Espir et al, 1966; De Castro and Campbell, 1967). In 23 patients with MS and paroxysmal neurological disturbances (other than trigeminal neuralgia) paroxysmal dysarthria and ataxia was the commonest type of attack (8 cases) (Espir and Millac, 1970). This was also the most common type of attack in our material (7 patients). In 2 patients the attacks were
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Kreindler et al. (1962), McAlpine (1965), Castaigne et al (1970) and Shibasaki and Kuroiwa (1974). In our first patient, the diagnosis was multiple sclerosis; in the second, acute disseminated encephalomyelitis was a more probable diagnosis. The main clinical features of the seizures were: (1) unilateral tonic spasm, either followed by, or preceded by, contralateral sensory disturbances; (2) an invariable temporal relation between the different sensory disturbances—a sensation of heat always preceded severe pain; and (3) brief duration and a high frequency of attacks. Case 1.—A woman, aged 53 when the seizures first occurred, had had a right-sided optic neuritis four years earlier. The seizures continued for about eight months. During this time neurological examination disclosed nothing abnormal except a residual loss of visual acuity in the right eye. Subsequently, the patient had several bouts of weakness in both legs, with partialrecoveryof muscle strength each time. She also had left-sided optic neuritis, bilateral sensory loss in the legs, and signs indicating disorder of the pyramidal tracts. The cerebrospinal fluid contained 57 mg of protein per 100 ml, and the gum-mastic test showed abnormal turbidity in 4 dilutions. The seizures were described as a "cramp" in the left leg, closely followed, first by a sensation of heat without pain, and then by a sensation of heat and severe pain in the right leg. On several occasions the feeling of heat and the pain preceded the tonic spasm. These attacks lasted about one minute, and occurred up to fifteen times a day. Two seizures were observed by us. The "cramp" was a tonic contraction of the muscles of the left leg. The calf became stiff and hard, and the toes were plantar-flexed. Quinine and diazepam (ValiumB) had no effect. After about four months the attacks were less frequent and the "cramp" component disappeared. The attacks then consisted only of a sensation of heat in the right leg. The attacks finally disappeared after another four months.
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the initial symptom of MS. Five patients were examined by us during the period in which the attacks occurred. All of these had signs referable to a brain-stem lesion. The occurrence of the attacks varied in different patients from three to four times a day to two hundred times a day, and the period during which the attacks occurred varied from one day to two years. In 3 patients the attacks were provoked by hyperventilation. Carbamazepine was used in 3 cases resulting in complete disappearance of the attacks. The following case report exemplifies how complicated the phenomena can be in some cases during an attack.
Paroxysmal Hemiataxia and Crossed Parotsthesice
Two patients had attacks consisting of ataxia in the right arm and leg preceded by a sensation of heat and/or pain in the left side of the face and left arm. This constellation of paroxysmal symptoms does not seem to have been described previously. Case 4.—A man, aged 53, had a twelve-year history of MS with a left-sided optic neuritis, panesthesiffi in the right arm, ataxia, weakness in the right leg and urgency of micturition. Neurological examination during the period of the attacks disclosed bilateral internuclear ophthalmoplegia, exaggerated reflexes in the right arm and leg, a right-sided extensor plantar response, and ataxia. The attacks started with a painful pricking sensation localized in the palate on the left side, and spreading to the whole left side of the face, and sometimes to the upper part of the left arm. This painful sensation was followed within a second by ataxia in the right arm and leg. He had to stop walking during the attacks; and when typing during an attack his right hand did not strike the right keys. EEG, recorded during five attacks, did not reveal anything pathological. The attacks lasted about ten seconds, and recurred aboutfivetimes an hour. The patient had noticed that the attacks recurred more frequently when he was stressed, and were often provoked when he rose quickly. He was treated with carbamazepine 200 mg x 2 after three months, and the attacks ceased within a day. Case 5.—A man, aged 36, had had a left-sided retrobulbar neuritis three years earlier. Neurological examination during the period of attacks did not reveal anything pathological except defective colour vision of the left eye and temporal pallor of the left disc.
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Case 3.—A woman, aged 30, had a two-year history of MS with three bouts of vertigo, double vision and tinnitus. During eight months she had attacks which lasted about one minute and recurred up to thirty to forty times a day. The attacks started with parasthesiae and a sensation of "heaviness" and "stiffness" in the right leg and right arm. Almost simultaneously she experienced double vision, ataxia and dysarthria. A few moments later she felt a sensation of heat in the left forearm. During the attack dysdiadochokinesis and incoordination were observed in the right arm, and the gait was broadbased and ataxic; she lifted the right leg high when walking. The attacks were provoked by hyperventilation and anxiety. After six months the attacks were less frequent, and ceased after another two months. Subsequently the patient had bouts of numbness and weakness in the limbs, apd a right-sided optic neuritis. She also had permanent ataxia, nystagmus and signs of disorder of the pyramidal tracts. At the age of 33 she complained of attacks of numbness and ataxia of the right leg. The attacks lasted half a minute, and recurred more than thirty times a day. They ceased after about ten months.
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The attacks started with a sensation of heat simultaneously in the left side of the face and neck and in the back of the left hand. The sensation of heat increased during several seconds, and was most intense behind the left eye. It was unpleasant, and sometimes painful. Within seconds from the onset of the attack the right arm became "clumsy" so that he was unable to write properly or to play the guitar or the concertina. Sometimes also slight ataxia developed in the right leg. At the same time he experienced dysarthria which increased during several seconds until his speech became incomprehensible. The attacks lasted ten to thirty seconds and recurred up to one hundred and sixty times a day. They continued for about two months. A double-blind trial showed that carbamazepine, but not placebo, was effective in controlling the attacks. On carbamazepine, 200 mg x 3, the attacks ceased completely.
Case 6.—A woman, aged 25, had for three years suffered clusters of attacks of double vision. From half an hour up to two hours she had frequent attacks of vertical diplopia; each attack lasted about one minute. The cluster of attacks of diplopia occurred every ten days. During the attacks her relatives noticed strabismus. She was treated with carbamazepine 200 mg x4 for nine months. Sporadic attacks of diplopia occurred during the first months of the treatment and then ceased. After stopping treatment she again had sporadic attacks of diplopia. The paroxysmal diplopia was the initial symptom of the disease. Later she experienced several bouts of numbness in the limbs, and periods with urgency of micturition. Colour vision of the left eye was defective. Agar-gel electrophoresis of the cerebrospinal fluid strengthened the diagnosis of MS.
Paroxysmal Numbness Two patients had attacks of paroxysmal numbness. One patient (Case 3) also had paroxysmal dysarthria and ataxia; her case history has been reported above. The other patient had paroxysmal numbness as the initial symptom of his undoubted MS at the age of 33. The numbness affected the left arm and leg. The attacks lasted less than ten seconds and recurred about five times a day. They ceased after seven months. Paroxysmal Pain The occurrence of pain as the predominant feature of paroxysmal attacks in MS has previously been reported by Espir and Millac (1970). One of our patients with tonic seizures had pain simultaneously in the arm and leg affected by the tonic contraction. Pain was also a feature of the spinal sensorimotor seizures. However, in one patient pain was the main symptom of the attacks.
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Paroxysmal Diplopia Diplopia often occurs in attacks of paroxysmal dysarthria and ataxia (see Case 3). As far as we are aware, it has not been reported previously as the single symptom. Three patients had paroxysmal diplopia. In 2 cases the attacks were the initial symptom of MS. In these cases diplopia was the single symptom; in one case the left hand was a little "clumsy" and the left leg somewhat ataxic during the attack. All these patients were examined by us during the period in which attacks occurred, and no pathological findings were observed. One patient had up to one hundred attacks a day for three months. Another patient had twenty to thirty attacks a day for ten months. Carbamazepine was effective in this case. The third case is reported below.
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Case 7.—A man, aged 28, had paroxysmal pain in the left arm as his first symptom of MS. The pain was of an aching character. Sometimes the pain affected also the left half of the trunk and the leg. He had also small twitchings in the left corner of his mouth and a feeling of "cramp" in the left hand during the attack. The attacks lasted five to ten seconds. They recurred up to ten to twelve times a day, and ceased after three months. During this period the patient had a slight weakness in the left arm, and the left hand was somewhat "clumsy." Subsequently, he had a bout of panesthesiae in the right half of the body and a bout of numbness in the face. The gum-mastic test showed pathological turbidity in four dilutions.
Case 8.—A woman, born 1940. Family history and past history irrelevant. In 1962 the patient experienced numbness in the left half of the face which lasted one day. Subsequently, the patient had right-sided optic neuritis, right-sided central facial palsy, two bouts of diplopia, and several bouts of weakness in the right and the left legs, with good recovery of muscle strength each time. She also had several bouts of transitory numbness and panesthesiae in the limbs and trunk. Lhermitte's sign was present for long periods. In 1963 the cerebrospinal fluid contained 58 mg of protein per 100 ml and the gum-mastic test showed abnormal turbidity in several dilutions. In 1972 neurological examination revealed moderate ataxia of the gait and slight ataxia of the arms in thefinger-to-nosetest. She had a lively horizontal nystagmus on lateral fixation to both sides, and ataxic eye movements. Attacks of itching first occurred in 1962. For several months she had attacks of itching in the front of both thighs. The attacks started on both sides at the same time, starting and ending abruptly. They lasted three to four minutes. The itching sensation was intense and similar to the itching she later experienced in the hands. She sometimes had fifteen to twenty attacks a day, but usually the frequency was lower. From 1967 on, she had attacks of itching in the hands. The first attacks were localized in her right index finger, but later she had periods with attacks either in the right or left hand. Within each period they were always in the same hand. The itching sometimes affected the fingertips, sometimes the palm of the hand, and sometimes the whole hand. Exceptionally, the hand and forearm were affected, and once itching affected the whole arm. The attack consisted of an intense itching sensation "beneath" the skin. The patient described the itching sensation as similar to an extremely itching midge bite. She experienced no pain or burning sensation. She could not resist the urge to claw and scratch although this gave no relief. She scratched with hard brushes, matchboxes and knives. She put her hands in the freezer and in hot water without relief. During the attack she got "mad" if anyone tried to stop her from scratching. The attacks started and ended abruptly: "as quick as a flash." After the itching had stopped she could feel a sensation of warmth in the hand, probably caused by the scratching. The duration of an attack was about three minutes. Drying the hands with a towel after washing often precipitated the attacks. The frequency of the attacks varied. At most she had fifteen attacks a day, but usually the frequency was much lower. Sometimes there were no attacks for several days or a week. The patient was treated with carbamazepine from October 1971. The dosage was 400 mg three times daily. During this treatment the attacks of itching were less frequent, shorter, and less intense, and Lhermitte's sign vanished. In December 1971 she temporarily discontinued the treatment, and until treatment was resumed the attacks of itching recurred several times a day, were very intense, and Lhermitte's sign reappeared. In the autumn of 1972 she had no attacks and the treatment was stopped in December 1972. Subsequently, she had only sporadic attacks of slight itching and Lhermitte's sign reappeared.
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Paroxysmal Itching An itching sensation with over-reaction to all stimuli may occasionally be observed as a sensory symptom in MS (McAlpine, 1972). However, as far as we are aware paroxysmal itching has not previously been reported.
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DISCUSSION
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Earlier and current conceptions of the pathogenesis of paroxysmal symptoms in MS can be grouped into the following categories: (1) The attacks are "positive" phenomena in Hughlings Jackson's sense. The primary event is thought to be a pathological discharge in subcortical grey matter in the central nervous system. This is the "epileptic" theory. An "epileptic" origin of tonic seizures was proposed by Guillain et al. (1928) and later by Storring (1940). Matthews (1958) also mentions the possibility that tonic seizures are focal epileptic fits originating in mesencephalic lesions. Similarly, Harrison and McGill (1969) suggest that attacks of paroxysmal dysarthria and ataxia are caused by a "build-up of post-synaptic facilitation from an (epileptic) discharge around a brain-stem plaque." (2) The attacks are "negative" phenomena in the Jacksonian sense. (i) Some types of attacks are thought to be caused by a simple loss of function, not involving any neuronal hyperactivity. Andermann et al. (1959) postulate that the underlying neurophysiological mechanism of paroxysmal attacks of dysarthria and ataxia "might be a conduction disorder determined by a rapidly reversible disturbance of metabolism of the myelin sheath or its supporting oligodendroglia." Espir et al. (1966) also propose the hypothesis that attacks of paroxysmal dysarthria and ataxia are caused by temporarily suspended function in axons in the earlier stages of demyelination. They suggest that the disordered function is caused by a minor degree of hypoxia which is too small to have any detectable effect on normal neurons. Similarly, Zeldowicz (1961) thought that a temporary paralysis of function, caused by transient vascular insufficiency or a rapidly reversible biochemical disturbance, caused paroxysmal akinesia. (ii) For the explanation of other types of attacks, for instance, tonic seizures, the "negative phenomenon" line of argument necessitates the concept of "release" due to deficient inhibition. The concept of "release" hyperactivity implies secondary pathological discharge in subcortical grey matter in the central nervous system. Matthews (1958) mentions this possible mechanism. Kreindler et al. (1962) ascribed tonic seizures to a lesion of the caudal portion of the reticular substance. Tonic seizures were considered to be a release phenomenon which could be triggered by changes in afferent input Castaigne et al. (1970) argue in the same way. (3) Some explanatory models are not easily fitted into the above scheme. In his extensive discussion of the pathogenesis of tonic seizures, Matthews (1958) stresses the resemblance of these attacks to tetany. He puts forward the hypothesis that "tetany implies a state of excitation of specific motor and sensory neurons, peripheral or central, usually induced by metabolic disorders, but also, on rare occasions, by structural lesions of the central nervous system." Determann (1892), Redlich (1929) and Decourt (1938) have also used the concept of tetany in discussing the pathogenesis of similar attacks.
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Lat. cortico" spinal tract
Temp. Pain Touch
FIG. 1.—Schematic drawing of transverse section of the spinal cord (modified from Foerster, 1927).
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The similarities between the different kinds of paroxysmal phenomena in MS—the brevity of the attacks, the frequency, the eliciting factors, the effect of anticonvulsive treatment—make it tempting to seek a unitary pathogenic hypothesis which could explain all the different kinds of attacks as arising from the same basic neuronal disturbance. Any hypothesis designed to explain the paroxysmal phenomena should obviously take into account the well-known fact that the pathological entity in MS— the demyelinated plaque—is localized in the white substance of the central nervous system. These considerations are fundamental in our thinking concerning the pathogenesis of paroxysmal attacks in MS. We propose that the paroxysmal phenomena in MS are caused by a transversely spreading, ephaptic activation of axons within a partially demyelinated lesion in fibre tracts somewhere in the central nervous system. Such a hypothesis is difficult to prove positively, but one way of testing it is to examine whether the proposed explanation is anatomically possible in the different kinds of attacks. In spinal sensorimotor seizures (Case 1) the sensory and motor disturbances are most readily explained by (1) a centrifugal stream of impulses along a motor path, and (2) a centripetal stream of impulses along a sensory path in the central nervous system. It seems probable that these streams of impulses are released from one locus because of the unvarying character of the seizures. The attacks can be described as "the Brown-Sequard syndrome in reverse," with the classical pattern of sensory and motor deficit replaced by corresponding sensory and motor irritative disturbances. A transversely spreading activation of axons within a lesion in the lateral funiculus of the spinal cord readily explains the crossed distribution of the tonic spasm and the sensory disturbances. The ipsilateral tonic spasm is thought to be caused by activation offibresin the lateral corticospinal tract. The invariable temporal relation between the different contralateral sensory disturbances—a sensation of heat always preceding a severe pain—may be explained by the spatial arrangement of pain and temperature fibres in the lateral funiculus of the spinal cord (fig. 1). In the cases of spinal sensorimotor seizures described by us, and in similar seizures reported by other authors, it is conspicuous that the crossed sensation experienced
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during the attacks is warmth, with a hot or burning quality, while the sensation of cold only seems to have been reported once (Shibasaki and Kuroiwa, 1974, Case 10). The explanation may be that the simultaneous activation of fibres conveying a sensation of warmth and cold in the lateral funiculus of the spinal cord evokes the sensation of heat. Hence, Alrutz (1900) suggested that the sensation of heat was a mixed sensation of warmth and "paradoxical" cold. Bipolar electrical stimulation within the anterior half of the cord in man elicited responses purely of temperature, usually heat, in 46 per cent of the responses in which any subjective sensation occurred; in 54 per cent the response was one of pain with or without a burning quality (Sweet, 1959). Corroborative evidence for a spinal origin of the sensorimotor seizures can be found by studying reports of similar seizures in the literature. A more or less complete Brown-Sequard syndrome was present in the cases reported by Schnabl (1897 and 1898), Oppenheim (1899), and Castaigne et al. (1970, Case 2). In the last-mentioned case it is interesting to note that a reversible Brown -S6quard syndrome, with motor symptoms on the left side, was present eleven weeks before the onset of the attacks. Furthermore, the attacks, consisting of a left-sided tonic spasm and a burning sensation in the right side of the body, were followed by transient weakness in the left side and right-sided analgesia and thermoanaesthesia; i.e. a "postictal Brown-Sequard syndrome." The third case described by Kreindler et al. (1962), is of special interest because of the detailed anatomo-pathological study. The attacks were usually ushered in by a right-sided burning sensation, which was immediately followed by a left-sided tonic seizure. At autopsy it was found that plaques were confined to the upper dorsal cord and the medulla at the level of the pyramidal decussation. The authors believed that the last-mentioned lesion was the important one for the pathogenesis of the attacks, because it damaged the caudal portion of the reticular substance. They clearly stated, however, that on the left side the lateral corticospinal tract and the lateral spinothalamic tract were included in the demyelinated area. As these tracts are still in close proximity at this level, the "ephaptic theory," involving a transversely spreading activation of fibres within these tracts, readily explains the crossed distribution of the motor and sensory phenomena. The fact that, sometimes at least, a burning sensation could also be felt, to a minor degree, on the left side, can possibly be understood in the light of an observation made by Sweet et al. (1950). They found that when pain was felt on bipolar electrical stimulation within the anterior half of the spinal cord, ipsilateral pain was produced in 11 per cent and bilateral pain in 6 per cent. In Japan, Kuroiwa and Shibasaki (Kuroiwa and Shibasaki, 1968; Shibasaki and Kuroiwa, 1974) have described so-called "painful tonic seizures" in patients with demyelinating disease. They stress the dominance of signs and symptoms referable to spinal cord lesions in all their patients. In both reports they postulate a spinal mechanism. In their earlier report (1968) they suggest that the sensory, but not the motor, symptoms are caused by transaxonal transmission.
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Case 9.—A man, aged 69, had been in good health until he was 62, when he fell on his head from a truck and fractured the odontoid. Since then he had walking difficulties and moderately decreased sensibility in the body below the neck. On bending the head forward or backward, or on turning it to either side he experienced "electric-like shocks" extending down the arms. Since he was 67 he had attacks of tonic contractions of the muscles in both lower legs. The attacks started with a series of "electric-like shocks" in the right lower leg, and simultaneously he felt numbness in the right hand. Almost immediately the "electric-like shocks" and the numbness spread to the left side. The paracsthesiae were closely followed, first, by a tonic contraction of the muscles of the right lower leg, and then by a tonic contraction of the muscles of the left lower leg. Sometimes, however, the attacks started on the left side and spread to the right side; and sometimes the tonic contraction only affected the muscles of one leg. During these contractions the calf became stiff, the foot was inverted and the toes were either plantar or dorsiflexed. The attacks lasted about one minute, and recurred up to ten tofifteentimes a day. They could be provoked by the movements of the neck which produced Lhermitte's sign. The attacks were followed by increased disturbance of sensibility in the legs, which lasted from a few minutes up to thirty minutes. Neurological examination revealed exaggerated tendon reflexes in both arms and in the right leg. The gait was spastic and the superficial and deep sensibility was decreased below the C2 level. On carbamazepine, 1 -4 g daily, the attacks ceased completely.
In this case there is no evidence of any other lesion in the central nervous system, except the obviously traumatic lesion in the upper cervical cord. Consequently, it seems safe to suppose that these tonic seizures had a spinal origin. However, it should be pointed out that the ephaptic theory, applied to tonic seizures, does not necessitate a spinal lesion; a lesion at any level in a motor path is sufficient. In connexion with the above-mentioned case, we wish to comment on the possible mechanism of Lhermitte's sign. This sign is known to be an indication of a pathological process affecting the posterior columns of the cervical spinal cord (Lhermitte et al., 1924; Alajouanine et al., 1949). The patients most often experience a direction of spread of the panesthesiae—down the back, down the arms, from the feet up to the trunk and upper limbs. This could be taken as an indication of a successive ephaptic activation of adjacent axons in the dorsal columns. It is interesting to note that carbamazepine is effective against the paraesthesiae associated with
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As a tonic seizure is, phenomenologically, identical with the motor component of a spinal sensorimotor seizure, it is natural for us to assume that tonic seizures can originate in a spinal lesion. Our second patient with spinal sensorimotor seizures (Ekbom et al., 1968) had left-sided tonic seizures for two months. After another three weeks her spinal sensorimotor seizures started. The motor component now had the same features as the previous tonic seizures and was left-sided. In this connexion Matthews' statement that 3 of his 4 patients with tonic seizures had a partial Brown-Sequard syndrome deserves mention. Kuroiwa and Araki (1963) reported autopsy findings in 3 patients with tonic seizures. They stressed the dominance of cervical cord lesions. As is usually the case in MS, however, there were also lesions at other levels of the central nervous system. We have recently seen a patient with a localized traumatic lesion of the cervical spinal cord who exhibited tonic seizures.
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Lhermitte's sign (Ekbom, 1971). We have been able to confirm Ekbom's observation in several cases. In paroxysmal hemiataxia and crossed paraesthesise (Cases 4 and 5) the attacks consisted of ataxia in the right arm and leg preceded by a sensation of heat and/or pain in the left side of the face and left arm. A transversely spreading activation of axons within a lesion in the upper part of the pons (fig. 2) may explain the crossed Brachlum conjunrtivum
'Q?
Lateral spinothalamic tract Med. lemnlscus Cortlcospinal and corticopontine tracts
Fro. 2.—Schematic drawing of transverse section of the pons, through motor trigeminal nucleus (according to standard textbooks of neuroanatomy).
distribution of ataxia and paraesthesiae. The ipsilateral ataxia may be explained by activation of fibres in the brachium conjunctivum. The contralateral sensation of heat and/or pain is thought to be caused by activation offibresin the ventral central trigeminal tract and in the dorsomedial part of the lateral spinothalamic tract In the pons the fibres in the lateral spinothalamic tract are segmentally arranged. Fibres conveying sensations of pain and temperature from the cervical segments are located dorsomedially in the lateral spinothalamic tract where they come in close contact with the ventral central trigeminal tract (Marburg, 1911; Wallenberg, 1911). A localized lesion within this area in the pons can, therefore, produce analgesia and thermal anaesthesia in one half of the face and in the shoulder and arm on the same side (Wallenberg, 1901; Bergmark, 1916; Foerster, 1927). The following case report shows that a single lesion in the pons can produce hemiataxia and crossed sensory disturbances with the same distribution as that seen in our 2 cases with paroxysmal hemiataxia and crossed paraesthesiae. Case 10.—A 44-year-old man with unremarkable past history. One morning he suddenly started sneezing and vertigo, double vision and walking difficulties developed within a few seconds. He also complained of a "pricking" sensation in the right half of the face and in the right arm. Neurological examination disclosed ataxia in the left arm and leg, altered sensibility in the right half of the face and in the right arm, dysarthria, left-sided palsy of the abducens nerve, skew deviation and nystagmus. The spinal fluid was normal. A four-vessel angiography revealed slight stenosis of the left vertebral artery at its origin from the subclavian artery.
The notion that an irritative lesion affecting a sensory path somewhere in the central nervous system can give rise to paraesthesiae or pain is generally accepted. Our new suggestion is that an irritative lesion affecting a fibre tract involved in
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So"
Ventr. spinocerebell. tr Motor nucl., N. V Sensory nucl., N. V Y Ventr. central trigeminal tract
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central motor control, for instance, the brachium conjunctivum, can produce ataxia. We thus propose that ataxia can be produced by hyperactivity as well as by hypoactivity in a path subserving motor control. It can readily be shown that ataxia, of a cerebellar type, can be produced by bombardment of central structures with excess impulses in proprioceptive paths.
In paroxysmal dysarthria and ataxia it is difficult to suggest an exact localization of the responsible lesion. However, there are no anatomical obstacles to the "ephaptic theory." Several localizations of an irritative lesion are possible, for instance, the decussation of the brachia conjunctiva. Paroxysmal diplopia could be explained, for instance, by discharges in abducens nerve fibres within the pons, or by discharges in the medial longitudinal fasciculus. In one of our patients we observed spasm of the left medial rectus muscle during some attacks, and skew deviation with vertical diplopia during other attacks. In this case discharges in the medial longitudinal fasciculus could explain the observed phenomena. Paroxysmal akinesia could possibly be explained by excessive discharges within an inhibitory path, subserving regulation of muscular tone. Paroxysmal numbness and pain are, obviously, readily accounted for by the ephaptic theory. Regarding our single case of paroxysmal itching it is difficult to explain why the subjective sensation was itch and not pain. An abundance of evidence exists to indicate that itching is closely related to cutaneous pain. The fibres conducting the quality of itching seem to be the same as, or at least closely following those which convey the sense of pain (Sweet, 1959). Torebjork (1974) recorded C-fibre activity with micro-electrodes from intact sensory fascicles in the human peroneal nerve. He found that sensations produced by cutaneous stimuli inducing intense afferent C-fibre activity were reported as "burning, or delayed, pain," whereas stimuli eliciting low frequency activity were often reported as "itch or burning itch." It is therefore possible that paroxysmal itching and paroxysmal pain are elicited from irritative lesions in the same fibre paths—differences in impulse patterns determining whether the sensation will be one of itch or of pain. SUMMARY
Twenty-two out of 235 patients with undoubted or suspected MS, treated at the Neurological Clinic, Uppsala, during the eight-year period, 1966-1973, had paroxysmal symptoms during the course of their disease. Paroxysmal dysarthria and ataxia (7 cases), and tonic seizures (5 cases) were the most common types of attacks. Some types of attacks (paroxysmal hemiataxia and crossed parssthesia;, paroxysmal itching, diplopia as the single paroxysmal symptom) do not seem to have been described previously. A patient with tonic seizures caused by a localized, traumatic lesion of the cervical spinal cord is also described.
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Vibration is known to be an efficient stimulus for intramuscular stretch receptors (Hagbarth, 1973). An electromechanical vibrator (stimulus amplitude 2-2 mm; frequency 130 Hz) was applied to the forearm of 5 normal adult subjects. In thefinger-to-nosetest an ataxia of cerebellar type was clearly seen in the vibrated arm during the first few trials. On further repetition of the manoeuvre the subjects were able to compensate for the abnormal influx of impulses.
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It is suggested that the paroxysmal phenomena in MS are caused by a transversely spreading ephaptic activation of axons within a partially demyelinated lesion in fibre tracts somewhere in the central nervous system. The different paroxysmal phenomena are discussed in the light of this hypothesis.
ANDERMANN, F., COSGROVE, J. B. R., LLOYD-SMITH, D., and WALTERS, A. M. (1959) Paroxysmal
dysarthria and ataxia in multiple sclerosis. Neurology, Minneap., 9, 211-215. ARNOULD, G., HARTEMANN, P., DUREUX, J-B. F TRIDON, P., and SCHMTTT, J. (1958) Scterose en
plaques et tetanic Des tdtanies neurogenes. Revue neurol., 98, 297-300. BEROMARK, G. (1916) Till fragan om de sensibla banorna i oblongata och pons. Svenska LOkSMik. Handl., 42,387-397. CASTAIGNE, P., CAMBIER, J., MASSON, M., BRUNET, P., LECHEVALLIER, B., DELAPORTE, P., and DEHEN, H.
(1970) Les manifestations motriccs paroxystiques de la sclerose en plaques. Presse mid., 78, 1921-1924. DE CASTRO, W., and CAMPBELL, J. (1967) Periodic ataxia. / . Am. med. Ass., 200,188-190. DECOURT, J. (1938) A propos d'un cas d'himitetanie d'origine cerdbrale. Considerations sur la physiopathologie de la titanic. Revue neurol., 70, 94-98. DETERMANN, H. (1892) Zwei Falle von Ruckenmarkserkrankung nach Influenza. Dt. Z. NervHeilk. 2, 106-112. EKBOM, K. (1971) Carbamazepine, a new symptomatic treatment for the parasthesice associated with Lhermitte's sign. Z. Neurol., 200, 341-344. EKBOM, K. A., WESTERBERG, C.-E., and OSTERMAN, P. O. (1968) Focal sensory-motor seizures of spinal origin. Lancet, 1, 67. ESPTR, M. L. E., and MILLAC, P. (1970) Treatment of paroxysmal disorders in multiple sclerosis with carbamazepine (Tegretol). / . Neurol. Neurosurg. Psychlat., 33, 528-531. , WATKINS, S. M., and SMITH, H. V. (1966) Paroxysmal dysarthria and other transient neurological disturbances in disseminated sclerosis. J. Neurol. Neurosurg. Psychiat., 29, 323-330. FABRI, S., and MILLEFIORINI, M. (1965) Crisi toniche in un caso di sclerosi multipla. Riv. Neurol., 35, 161-168. FOERSTER, O. (1927) Die Leitungsbahnen des Schmerzgefuhls und die chirurgische Behandlung der Schmerzzustande. Beitr. klin. Chir., Sonderb., 1, 1-360. GUILLAIN, G., ALAJOUANINE, TH., BERTRAND, I., and GARCIN, R, (1928) Sur une forme anatomo-
cliniquc speciale de neuro-my^lite optique necrotique aigue avec crises toniques tetanoides. Annls Mid., 24, 24-57. HAOBARTH, K.-E. (1973) The effect of muscle vibration in normal man and in patients with motor disorders. In: "New Developments in EMG and Clinical Neurophysiology." Edited by J. E. Desmedt. Brussels: Kargcr, vol. 3, pp. 428-443. HARRISON, M., and MCGILL, J. I. (1969) Transient neurological disturbances in disseminated sclerosis: a case report. / . Neurol. Neurosurg. Psychiat., 32, 230-232. JOYNT, R. J., and GREEN, D. (1962) Tonic seizures as a manifestation of multiple sclerosis. Archs Neurol., Chicago, 6, 293-299. KREINDLER, A., CARDAS, M., PETRESCO, AR., and BOTEZ, M. I. (1962) Considerations sur l'6tiopathogenie
des crises toniques dans l'encephalomyilite dissiminee. Revue neurol., 107, 353-369. KUROIWA, Y., and ARAKI, S. (1963) Lhermitte's sign and reflex tonic spasm in demyelinating diseases with special reference to their localizing value. Kyushu J. med. ScL, 14, 29-38. , and SHIBASAKI, H. (1968) Painful tonic seizure in multiple sclerosis. Treatment with diphenylhydantoin and carbamazepine. Folia psychiat. neurol. jap., 22, 107-119.
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REFERENCES ALAJOUANINE, TH., THUREL, R., and PAPAIOANOU, C. (1949) La doulcur a type de decharge ilectrique, provoquee par la flexion de la tfite et parcourant le corps de haut en bas. Revue neurol., 81, 89-97. ALRUTZ. S. (1900) Studien auf dem Gebiete der Temperatursinne. Skand. Arch. Physiol, 10, 340-352.
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{Received November 12,1974)
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LANCE, J. W. (1963) Sporadic and familial varieties of tonic seizures. /. Newrol. Neurosurg. Psychiat., 26,51-59. LHERMTTTE, J., BOLLAK, J., and NICOLAS, M. (1924) Les douleurs a type de decharge 61ectrique cons4cutives a la flexion o£phalique dans la scterose en plaques: Un cas de forme sensitive de la scldrose multiple. Revue neurol., 31, 56-62. LUGARESI, E., BOTTAZZL G., and GHEDINI, G. (1962) Manifestazioni atassico-disartriche ricorrenti in corso di sclerosi multipla. Note Riv. Psichtoi., 55, 271-276. MCALPINE, D. (1965) In: "Multiple Sclerosis: A Reappraisal." Edited by D. McAlpine, C. E. Lumsden and E. D. Acheson. Edinburgh: Livingstone, p. 147. (1972) In: "Multiple Sclerosis: A Reappraisal." Edited by D. McAlpine, C. E. Lumsden and E. D . Acheson. 2nd Ed. Baltimore: Williams and Wilkins, pp. 132-196. MARBURO, O. (1911) Uber die neueren Fortschritte in der topischen Diagnostik des Pons und der OblongaUu Dt. Z. NervHeilk., 41, 41-91. MATTHEWS, W. B. (1958) Tonic seizures in disseminated sclerosis. Brain, 81,193-206. OPPENHEIM, H. (1899) Zur Brown-Sequard'schen LShmung. Arch. Anat. Physiol, Suppl., 15,1-30. PARTER, H. L. (1946) Periodic ataxia. Coll. Pap. Mayo Clin., 28, 642-645. REDUCH, E. (1929) Zur Klinik der Hemitctanie mit Er8rterungen Ober den Ausl&sungort der tetanischeD Krampfe. Z. ges. Neurol. Psychiat., 120, 236-264. SCHNABL, J. (1897) Wiener medicinischcr Club. Sitzung vom 24. Nov. 1897. Wien. kiln. Wschr., 10,. 1112-1113. (1898) Wiener medidnischer d u b . Sitzung vom 9. Februar 1898. Wien. klin. Wschr., 11, 223. SHIBASAKI, H., and KuRorwA, Y. (1974) Painful tonic seizure in multiple sclerosis. Archs Neurol, Chicago* 30, 47-51. SPILLER, W. G. (1927) Subcortical epilepsy. Brain, 50,171-187. STORRINO, G. E. (1940) Epilepsie und multiple Sklerose: Zugleich ein Beitrag zur Differentialdiagnose der Epilepsie. Arch. Psychiat. NervKrankh., 112, 45-75. SWEET, W. H. (1959) Pain. In: "Handbook of Physiology. Sect. 1: Neurophysiology." Vol.1. Edited by J. Field, H. W. Magoun and V. E. Hall. Washington D.C.: American Physiological Society, pp. 459-506. , WHITE, J. C , SELVERSTONE, B., and NOOES, R. (1950) Sensory responses from anterior roots and from surface and interior of spinal cord in man. Trans. Am. neurol. Ass., 75,165-169. TOREBJORK, E. H. (1974) Afferent C units responding to mechanical, thermal and chemical stimuli in human non-glabrous skin. Ada physiol. scand., 92, 374-390. WALLENBERG, A. (1901) KJinische BeitrSge zur Diagnostik acuter Herderkranlcungen des verWngerten Markes und der Brucke. Dt. Z. NervHeilk., 19, 227-248. (1911) Ncuere Fortschritte in der topischen Diagnostik des Pons und der Oblongata. Dt. Z. NervHeilk., 41, 8-41. ZELDOWICZ, L. (1961) Paroxysmal motor episodes as early manifestations of multiple sclerosis. Can. med. Ass. J., 84, 937-941.
PAROXYSMAL ATTACKS IN MULTIPLE SCLEROSIS BY
(From the Department of Neurology, University Hospital, Uppsala)
INTRODUCTION
THE occurrence of paroxysmal attacks during the course of multiple sclerosis (MS) is now well known (McAlpine, 1972). Most reports have dealt with the so-called tonic seizures. Although there were some early reports on tonic seizures in cases of probable multiple sclerosis (Determann, 1892; Guillain et al, 1928; Redlich, 1929; Decourt, 1938; Storring, 1940; Arnould et al., 1958) it was Matthews in 1958 who established the firm connexion between this particular form of attacks and MS. In 1959 Andermann et al. described paroxysmal dysarthria and ataxia which is probably one of the commonest types orpafoxysmal attacks in MS. Earner descriptions of similar or identical attacks were given by Storring (1940, Case 7) and by Parker (1946) who used the name periodic ataxia. Less common types of attacks are paroxysmal akinesia (Zeldowicz, 1961) and paroxysmal paraesthesiae and paroxysmal pain in limbs (Espir and Millac, 1970). We have previously reported an unusual type of attack, focal sensorimotor seizures of spinal origin (Ekbom et al., 1968). In that paper we proposed the hypothesis that the attacks were caused by a transversely spreading activation of damaged axons in fibre tracts of the spinal cord. Further clinical studies of MS patients exhibiting paroxysmal attaclcs of different kinds have led us to believe that this pathogenic mechanism might be operative in several other types of attacks in MS. In this paper we wish to report our collected experience of paroxysmal attacks in MS. Some types of attack have not been previously described. The different paroxysmal phenomena will be discussed in the light of our proposed hypothesis of the pathogenic mechanism. MATERIAL AND METHODS
Twenty-two patients, 14 women and 8 men, with paroxysmal attacks, were studied (Table I). They were collected from a total of 235 patients with undoubted or suspected MS, treated at the Neurological Clinic, Uppsala, during the eight-year period, 1966-1973. 14
BRAIN—VOL. XCVm
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TABLE L—TYPES OF PAROXYSMAL SEIZURES IN 22 CASES WITH MULTIPLE SCLEROSIS, THE ATTACKS ARE DENOMINATED BY THEIR MAIN SYMPTOM
Type
No. of patients
. ^ Tonic seizures
5
Spinal sensorimotor seizures
1
Paroxysmal akinesia
1
y,' Paroxysmal dysarthria and ataxia Paroxysmal hemiataxia and crossed panesthesiae
7* 2 3
Paroxysmal numbness
2*
Paroxysmal pain
1
Paroxysmal itching ' 1 •One patient (Case 3) had during one period paroxysmal dysarthria and ataxia and during another period paroxysmal numbness.
Thus, about 9 per cent of our patients had paroxysmal symptoms during the course of their disease. This figure should be regarded only as an approximation. For instance, outpatients were not included in the study, and biasing selection factors may have been operative. The patients with paroxysmal symptoms were interviewed and examined by one or other of us. RESULTS AND CASE REPORTS
Tonic Seizures The study of tonic seizures in MS by Matthews (1958) was followed by several reports of similar cases (Joynt and Green, 1962; Kreindler et ah, 1962; Kuroiwa and Araki, 1963; Lance, 1963; Fabri and Millefiorini, 1965; Kuroiwa and Shibasaki, 1938; Castaigne et ai, 1970; Espir and Millac, 1970; Shibasaki and Kuroiwa, 1974). The attacks of tonic seizures that we observed in our patients were similar to those previously reported. As can be seen from the table, tonic seizures were the second most common type of attacks (5 patients). In no case were the attacks the initial symptom of the disease. The seizures were painful in one case. This patient also experienced paraesthesiae in the right arm and leg immediately preceding the tonic contraction. The tendon reflexes were exaggerated in the right arm in this patient. Two other patients had signs of bilateral disorder of the pyramidal tracts. In 2 cases examination during the period of attacks did not reveal anything pathological. The occurrence of the attacks varied in different patients from four to five attacks during three years, up to thirty attacks a day for one month. Spinal Sensorimotor Seizures In 1968 we reported 2 cases of spinal sensorimotor seizures (Ekbom et al., 1968). We have been unable to find any case reports of patients whose symptoms and signs corresponded exactly to those observed in our patients but similar seizures have been observed by Schnabl (1897 and 1898), Oppenheim (1899), Spiller (1927),
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Paroxysmal diplopia
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Paroxysmal Akinesia Although Zeldowicz in 1961 could report as many as 12 cases of paroxysmal akinesia or sudden loss of tone, there seems to have been only one subsequent report, in which 3 similar cases were described (Castaigne et al., 1970). We now report one more case. Case 2.—A man, aged 45, had had during three years preceding the period with the attacks, a bout of transient weakness and numbness in the legs, a bout of numbness in the left arm, and Lhermitte's sign. The diagnosis of MS was strengthened by the result of agar-gel eJectrophoresis of the cerebrospinal fluid. The attacks consisted of a sudden sensation of the right knee being "locked." He lost the tone of the muscles of the right leg, which made him stop for a few seconds. The maxima] recurrence of attacks was thirty times a day, and they ceased after about six months. With carbamazepine (TegretolR) 200 mg x 3, the frequency was reduced to 1/3. Unfortunately, an allergic skin reaction developed after fourteen days, which made further treatment impossible. Paroxysmal Dysarthria and Ataxia Several previous reports have dealt with paroxysmal dysarthria and ataxia (Andermann et al, 1959; Lugaresi et al, 1962; Espir et al, 1966; De Castro and Campbell, 1967). In 23 patients with MS and paroxysmal neurological disturbances (other than trigeminal neuralgia) paroxysmal dysarthria and ataxia was the commonest type of attack (8 cases) (Espir and Millac, 1970). This was also the most common type of attack in our material (7 patients). In 2 patients the attacks were
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Kreindler et al. (1962), McAlpine (1965), Castaigne et al (1970) and Shibasaki and Kuroiwa (1974). In our first patient, the diagnosis was multiple sclerosis; in the second, acute disseminated encephalomyelitis was a more probable diagnosis. The main clinical features of the seizures were: (1) unilateral tonic spasm, either followed by, or preceded by, contralateral sensory disturbances; (2) an invariable temporal relation between the different sensory disturbances—a sensation of heat always preceded severe pain; and (3) brief duration and a high frequency of attacks. Case 1.—A woman, aged 53 when the seizures first occurred, had had a right-sided optic neuritis four years earlier. The seizures continued for about eight months. During this time neurological examination disclosed nothing abnormal except a residual loss of visual acuity in the right eye. Subsequently, the patient had several bouts of weakness in both legs, with partialrecoveryof muscle strength each time. She also had left-sided optic neuritis, bilateral sensory loss in the legs, and signs indicating disorder of the pyramidal tracts. The cerebrospinal fluid contained 57 mg of protein per 100 ml, and the gum-mastic test showed abnormal turbidity in 4 dilutions. The seizures were described as a "cramp" in the left leg, closely followed, first by a sensation of heat without pain, and then by a sensation of heat and severe pain in the right leg. On several occasions the feeling of heat and the pain preceded the tonic spasm. These attacks lasted about one minute, and occurred up to fifteen times a day. Two seizures were observed by us. The "cramp" was a tonic contraction of the muscles of the left leg. The calf became stiff and hard, and the toes were plantar-flexed. Quinine and diazepam (ValiumB) had no effect. After about four months the attacks were less frequent and the "cramp" component disappeared. The attacks then consisted only of a sensation of heat in the right leg. The attacks finally disappeared after another four months.
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the initial symptom of MS. Five patients were examined by us during the period in which the attacks occurred. All of these had signs referable to a brain-stem lesion. The occurrence of the attacks varied in different patients from three to four times a day to two hundred times a day, and the period during which the attacks occurred varied from one day to two years. In 3 patients the attacks were provoked by hyperventilation. Carbamazepine was used in 3 cases resulting in complete disappearance of the attacks. The following case report exemplifies how complicated the phenomena can be in some cases during an attack.
Paroxysmal Hemiataxia and Crossed Parotsthesice
Two patients had attacks consisting of ataxia in the right arm and leg preceded by a sensation of heat and/or pain in the left side of the face and left arm. This constellation of paroxysmal symptoms does not seem to have been described previously. Case 4.—A man, aged 53, had a twelve-year history of MS with a left-sided optic neuritis, panesthesiffi in the right arm, ataxia, weakness in the right leg and urgency of micturition. Neurological examination during the period of the attacks disclosed bilateral internuclear ophthalmoplegia, exaggerated reflexes in the right arm and leg, a right-sided extensor plantar response, and ataxia. The attacks started with a painful pricking sensation localized in the palate on the left side, and spreading to the whole left side of the face, and sometimes to the upper part of the left arm. This painful sensation was followed within a second by ataxia in the right arm and leg. He had to stop walking during the attacks; and when typing during an attack his right hand did not strike the right keys. EEG, recorded during five attacks, did not reveal anything pathological. The attacks lasted about ten seconds, and recurred aboutfivetimes an hour. The patient had noticed that the attacks recurred more frequently when he was stressed, and were often provoked when he rose quickly. He was treated with carbamazepine 200 mg x 2 after three months, and the attacks ceased within a day. Case 5.—A man, aged 36, had had a left-sided retrobulbar neuritis three years earlier. Neurological examination during the period of attacks did not reveal anything pathological except defective colour vision of the left eye and temporal pallor of the left disc.
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Case 3.—A woman, aged 30, had a two-year history of MS with three bouts of vertigo, double vision and tinnitus. During eight months she had attacks which lasted about one minute and recurred up to thirty to forty times a day. The attacks started with parasthesiae and a sensation of "heaviness" and "stiffness" in the right leg and right arm. Almost simultaneously she experienced double vision, ataxia and dysarthria. A few moments later she felt a sensation of heat in the left forearm. During the attack dysdiadochokinesis and incoordination were observed in the right arm, and the gait was broadbased and ataxic; she lifted the right leg high when walking. The attacks were provoked by hyperventilation and anxiety. After six months the attacks were less frequent, and ceased after another two months. Subsequently the patient had bouts of numbness and weakness in the limbs, apd a right-sided optic neuritis. She also had permanent ataxia, nystagmus and signs of disorder of the pyramidal tracts. At the age of 33 she complained of attacks of numbness and ataxia of the right leg. The attacks lasted half a minute, and recurred more than thirty times a day. They ceased after about ten months.
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The attacks started with a sensation of heat simultaneously in the left side of the face and neck and in the back of the left hand. The sensation of heat increased during several seconds, and was most intense behind the left eye. It was unpleasant, and sometimes painful. Within seconds from the onset of the attack the right arm became "clumsy" so that he was unable to write properly or to play the guitar or the concertina. Sometimes also slight ataxia developed in the right leg. At the same time he experienced dysarthria which increased during several seconds until his speech became incomprehensible. The attacks lasted ten to thirty seconds and recurred up to one hundred and sixty times a day. They continued for about two months. A double-blind trial showed that carbamazepine, but not placebo, was effective in controlling the attacks. On carbamazepine, 200 mg x 3, the attacks ceased completely.
Case 6.—A woman, aged 25, had for three years suffered clusters of attacks of double vision. From half an hour up to two hours she had frequent attacks of vertical diplopia; each attack lasted about one minute. The cluster of attacks of diplopia occurred every ten days. During the attacks her relatives noticed strabismus. She was treated with carbamazepine 200 mg x4 for nine months. Sporadic attacks of diplopia occurred during the first months of the treatment and then ceased. After stopping treatment she again had sporadic attacks of diplopia. The paroxysmal diplopia was the initial symptom of the disease. Later she experienced several bouts of numbness in the limbs, and periods with urgency of micturition. Colour vision of the left eye was defective. Agar-gel electrophoresis of the cerebrospinal fluid strengthened the diagnosis of MS.
Paroxysmal Numbness Two patients had attacks of paroxysmal numbness. One patient (Case 3) also had paroxysmal dysarthria and ataxia; her case history has been reported above. The other patient had paroxysmal numbness as the initial symptom of his undoubted MS at the age of 33. The numbness affected the left arm and leg. The attacks lasted less than ten seconds and recurred about five times a day. They ceased after seven months. Paroxysmal Pain The occurrence of pain as the predominant feature of paroxysmal attacks in MS has previously been reported by Espir and Millac (1970). One of our patients with tonic seizures had pain simultaneously in the arm and leg affected by the tonic contraction. Pain was also a feature of the spinal sensorimotor seizures. However, in one patient pain was the main symptom of the attacks.
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Paroxysmal Diplopia Diplopia often occurs in attacks of paroxysmal dysarthria and ataxia (see Case 3). As far as we are aware, it has not been reported previously as the single symptom. Three patients had paroxysmal diplopia. In 2 cases the attacks were the initial symptom of MS. In these cases diplopia was the single symptom; in one case the left hand was a little "clumsy" and the left leg somewhat ataxic during the attack. All these patients were examined by us during the period in which attacks occurred, and no pathological findings were observed. One patient had up to one hundred attacks a day for three months. Another patient had twenty to thirty attacks a day for ten months. Carbamazepine was effective in this case. The third case is reported below.
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Case 7.—A man, aged 28, had paroxysmal pain in the left arm as his first symptom of MS. The pain was of an aching character. Sometimes the pain affected also the left half of the trunk and the leg. He had also small twitchings in the left corner of his mouth and a feeling of "cramp" in the left hand during the attack. The attacks lasted five to ten seconds. They recurred up to ten to twelve times a day, and ceased after three months. During this period the patient had a slight weakness in the left arm, and the left hand was somewhat "clumsy." Subsequently, he had a bout of panesthesiae in the right half of the body and a bout of numbness in the face. The gum-mastic test showed pathological turbidity in four dilutions.
Case 8.—A woman, born 1940. Family history and past history irrelevant. In 1962 the patient experienced numbness in the left half of the face which lasted one day. Subsequently, the patient had right-sided optic neuritis, right-sided central facial palsy, two bouts of diplopia, and several bouts of weakness in the right and the left legs, with good recovery of muscle strength each time. She also had several bouts of transitory numbness and panesthesiae in the limbs and trunk. Lhermitte's sign was present for long periods. In 1963 the cerebrospinal fluid contained 58 mg of protein per 100 ml and the gum-mastic test showed abnormal turbidity in several dilutions. In 1972 neurological examination revealed moderate ataxia of the gait and slight ataxia of the arms in thefinger-to-nosetest. She had a lively horizontal nystagmus on lateral fixation to both sides, and ataxic eye movements. Attacks of itching first occurred in 1962. For several months she had attacks of itching in the front of both thighs. The attacks started on both sides at the same time, starting and ending abruptly. They lasted three to four minutes. The itching sensation was intense and similar to the itching she later experienced in the hands. She sometimes had fifteen to twenty attacks a day, but usually the frequency was lower. From 1967 on, she had attacks of itching in the hands. The first attacks were localized in her right index finger, but later she had periods with attacks either in the right or left hand. Within each period they were always in the same hand. The itching sometimes affected the fingertips, sometimes the palm of the hand, and sometimes the whole hand. Exceptionally, the hand and forearm were affected, and once itching affected the whole arm. The attack consisted of an intense itching sensation "beneath" the skin. The patient described the itching sensation as similar to an extremely itching midge bite. She experienced no pain or burning sensation. She could not resist the urge to claw and scratch although this gave no relief. She scratched with hard brushes, matchboxes and knives. She put her hands in the freezer and in hot water without relief. During the attack she got "mad" if anyone tried to stop her from scratching. The attacks started and ended abruptly: "as quick as a flash." After the itching had stopped she could feel a sensation of warmth in the hand, probably caused by the scratching. The duration of an attack was about three minutes. Drying the hands with a towel after washing often precipitated the attacks. The frequency of the attacks varied. At most she had fifteen attacks a day, but usually the frequency was much lower. Sometimes there were no attacks for several days or a week. The patient was treated with carbamazepine from October 1971. The dosage was 400 mg three times daily. During this treatment the attacks of itching were less frequent, shorter, and less intense, and Lhermitte's sign vanished. In December 1971 she temporarily discontinued the treatment, and until treatment was resumed the attacks of itching recurred several times a day, were very intense, and Lhermitte's sign reappeared. In the autumn of 1972 she had no attacks and the treatment was stopped in December 1972. Subsequently, she had only sporadic attacks of slight itching and Lhermitte's sign reappeared.
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Paroxysmal Itching An itching sensation with over-reaction to all stimuli may occasionally be observed as a sensory symptom in MS (McAlpine, 1972). However, as far as we are aware paroxysmal itching has not previously been reported.
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DISCUSSION
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Earlier and current conceptions of the pathogenesis of paroxysmal symptoms in MS can be grouped into the following categories: (1) The attacks are "positive" phenomena in Hughlings Jackson's sense. The primary event is thought to be a pathological discharge in subcortical grey matter in the central nervous system. This is the "epileptic" theory. An "epileptic" origin of tonic seizures was proposed by Guillain et al. (1928) and later by Storring (1940). Matthews (1958) also mentions the possibility that tonic seizures are focal epileptic fits originating in mesencephalic lesions. Similarly, Harrison and McGill (1969) suggest that attacks of paroxysmal dysarthria and ataxia are caused by a "build-up of post-synaptic facilitation from an (epileptic) discharge around a brain-stem plaque." (2) The attacks are "negative" phenomena in the Jacksonian sense. (i) Some types of attacks are thought to be caused by a simple loss of function, not involving any neuronal hyperactivity. Andermann et al. (1959) postulate that the underlying neurophysiological mechanism of paroxysmal attacks of dysarthria and ataxia "might be a conduction disorder determined by a rapidly reversible disturbance of metabolism of the myelin sheath or its supporting oligodendroglia." Espir et al. (1966) also propose the hypothesis that attacks of paroxysmal dysarthria and ataxia are caused by temporarily suspended function in axons in the earlier stages of demyelination. They suggest that the disordered function is caused by a minor degree of hypoxia which is too small to have any detectable effect on normal neurons. Similarly, Zeldowicz (1961) thought that a temporary paralysis of function, caused by transient vascular insufficiency or a rapidly reversible biochemical disturbance, caused paroxysmal akinesia. (ii) For the explanation of other types of attacks, for instance, tonic seizures, the "negative phenomenon" line of argument necessitates the concept of "release" due to deficient inhibition. The concept of "release" hyperactivity implies secondary pathological discharge in subcortical grey matter in the central nervous system. Matthews (1958) mentions this possible mechanism. Kreindler et al. (1962) ascribed tonic seizures to a lesion of the caudal portion of the reticular substance. Tonic seizures were considered to be a release phenomenon which could be triggered by changes in afferent input Castaigne et al. (1970) argue in the same way. (3) Some explanatory models are not easily fitted into the above scheme. In his extensive discussion of the pathogenesis of tonic seizures, Matthews (1958) stresses the resemblance of these attacks to tetany. He puts forward the hypothesis that "tetany implies a state of excitation of specific motor and sensory neurons, peripheral or central, usually induced by metabolic disorders, but also, on rare occasions, by structural lesions of the central nervous system." Determann (1892), Redlich (1929) and Decourt (1938) have also used the concept of tetany in discussing the pathogenesis of similar attacks.
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Lat. cortico" spinal tract
Temp. Pain Touch
FIG. 1.—Schematic drawing of transverse section of the spinal cord (modified from Foerster, 1927).
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The similarities between the different kinds of paroxysmal phenomena in MS—the brevity of the attacks, the frequency, the eliciting factors, the effect of anticonvulsive treatment—make it tempting to seek a unitary pathogenic hypothesis which could explain all the different kinds of attacks as arising from the same basic neuronal disturbance. Any hypothesis designed to explain the paroxysmal phenomena should obviously take into account the well-known fact that the pathological entity in MS— the demyelinated plaque—is localized in the white substance of the central nervous system. These considerations are fundamental in our thinking concerning the pathogenesis of paroxysmal attacks in MS. We propose that the paroxysmal phenomena in MS are caused by a transversely spreading, ephaptic activation of axons within a partially demyelinated lesion in fibre tracts somewhere in the central nervous system. Such a hypothesis is difficult to prove positively, but one way of testing it is to examine whether the proposed explanation is anatomically possible in the different kinds of attacks. In spinal sensorimotor seizures (Case 1) the sensory and motor disturbances are most readily explained by (1) a centrifugal stream of impulses along a motor path, and (2) a centripetal stream of impulses along a sensory path in the central nervous system. It seems probable that these streams of impulses are released from one locus because of the unvarying character of the seizures. The attacks can be described as "the Brown-Sequard syndrome in reverse," with the classical pattern of sensory and motor deficit replaced by corresponding sensory and motor irritative disturbances. A transversely spreading activation of axons within a lesion in the lateral funiculus of the spinal cord readily explains the crossed distribution of the tonic spasm and the sensory disturbances. The ipsilateral tonic spasm is thought to be caused by activation offibresin the lateral corticospinal tract. The invariable temporal relation between the different contralateral sensory disturbances—a sensation of heat always preceding a severe pain—may be explained by the spatial arrangement of pain and temperature fibres in the lateral funiculus of the spinal cord (fig. 1). In the cases of spinal sensorimotor seizures described by us, and in similar seizures reported by other authors, it is conspicuous that the crossed sensation experienced
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during the attacks is warmth, with a hot or burning quality, while the sensation of cold only seems to have been reported once (Shibasaki and Kuroiwa, 1974, Case 10). The explanation may be that the simultaneous activation of fibres conveying a sensation of warmth and cold in the lateral funiculus of the spinal cord evokes the sensation of heat. Hence, Alrutz (1900) suggested that the sensation of heat was a mixed sensation of warmth and "paradoxical" cold. Bipolar electrical stimulation within the anterior half of the cord in man elicited responses purely of temperature, usually heat, in 46 per cent of the responses in which any subjective sensation occurred; in 54 per cent the response was one of pain with or without a burning quality (Sweet, 1959). Corroborative evidence for a spinal origin of the sensorimotor seizures can be found by studying reports of similar seizures in the literature. A more or less complete Brown-Sequard syndrome was present in the cases reported by Schnabl (1897 and 1898), Oppenheim (1899), and Castaigne et al. (1970, Case 2). In the last-mentioned case it is interesting to note that a reversible Brown -S6quard syndrome, with motor symptoms on the left side, was present eleven weeks before the onset of the attacks. Furthermore, the attacks, consisting of a left-sided tonic spasm and a burning sensation in the right side of the body, were followed by transient weakness in the left side and right-sided analgesia and thermoanaesthesia; i.e. a "postictal Brown-Sequard syndrome." The third case described by Kreindler et al. (1962), is of special interest because of the detailed anatomo-pathological study. The attacks were usually ushered in by a right-sided burning sensation, which was immediately followed by a left-sided tonic seizure. At autopsy it was found that plaques were confined to the upper dorsal cord and the medulla at the level of the pyramidal decussation. The authors believed that the last-mentioned lesion was the important one for the pathogenesis of the attacks, because it damaged the caudal portion of the reticular substance. They clearly stated, however, that on the left side the lateral corticospinal tract and the lateral spinothalamic tract were included in the demyelinated area. As these tracts are still in close proximity at this level, the "ephaptic theory," involving a transversely spreading activation of fibres within these tracts, readily explains the crossed distribution of the motor and sensory phenomena. The fact that, sometimes at least, a burning sensation could also be felt, to a minor degree, on the left side, can possibly be understood in the light of an observation made by Sweet et al. (1950). They found that when pain was felt on bipolar electrical stimulation within the anterior half of the spinal cord, ipsilateral pain was produced in 11 per cent and bilateral pain in 6 per cent. In Japan, Kuroiwa and Shibasaki (Kuroiwa and Shibasaki, 1968; Shibasaki and Kuroiwa, 1974) have described so-called "painful tonic seizures" in patients with demyelinating disease. They stress the dominance of signs and symptoms referable to spinal cord lesions in all their patients. In both reports they postulate a spinal mechanism. In their earlier report (1968) they suggest that the sensory, but not the motor, symptoms are caused by transaxonal transmission.
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Case 9.—A man, aged 69, had been in good health until he was 62, when he fell on his head from a truck and fractured the odontoid. Since then he had walking difficulties and moderately decreased sensibility in the body below the neck. On bending the head forward or backward, or on turning it to either side he experienced "electric-like shocks" extending down the arms. Since he was 67 he had attacks of tonic contractions of the muscles in both lower legs. The attacks started with a series of "electric-like shocks" in the right lower leg, and simultaneously he felt numbness in the right hand. Almost immediately the "electric-like shocks" and the numbness spread to the left side. The paracsthesiae were closely followed, first, by a tonic contraction of the muscles of the right lower leg, and then by a tonic contraction of the muscles of the left lower leg. Sometimes, however, the attacks started on the left side and spread to the right side; and sometimes the tonic contraction only affected the muscles of one leg. During these contractions the calf became stiff, the foot was inverted and the toes were either plantar or dorsiflexed. The attacks lasted about one minute, and recurred up to ten tofifteentimes a day. They could be provoked by the movements of the neck which produced Lhermitte's sign. The attacks were followed by increased disturbance of sensibility in the legs, which lasted from a few minutes up to thirty minutes. Neurological examination revealed exaggerated tendon reflexes in both arms and in the right leg. The gait was spastic and the superficial and deep sensibility was decreased below the C2 level. On carbamazepine, 1 -4 g daily, the attacks ceased completely.
In this case there is no evidence of any other lesion in the central nervous system, except the obviously traumatic lesion in the upper cervical cord. Consequently, it seems safe to suppose that these tonic seizures had a spinal origin. However, it should be pointed out that the ephaptic theory, applied to tonic seizures, does not necessitate a spinal lesion; a lesion at any level in a motor path is sufficient. In connexion with the above-mentioned case, we wish to comment on the possible mechanism of Lhermitte's sign. This sign is known to be an indication of a pathological process affecting the posterior columns of the cervical spinal cord (Lhermitte et al., 1924; Alajouanine et al., 1949). The patients most often experience a direction of spread of the panesthesiae—down the back, down the arms, from the feet up to the trunk and upper limbs. This could be taken as an indication of a successive ephaptic activation of adjacent axons in the dorsal columns. It is interesting to note that carbamazepine is effective against the paraesthesiae associated with
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As a tonic seizure is, phenomenologically, identical with the motor component of a spinal sensorimotor seizure, it is natural for us to assume that tonic seizures can originate in a spinal lesion. Our second patient with spinal sensorimotor seizures (Ekbom et al., 1968) had left-sided tonic seizures for two months. After another three weeks her spinal sensorimotor seizures started. The motor component now had the same features as the previous tonic seizures and was left-sided. In this connexion Matthews' statement that 3 of his 4 patients with tonic seizures had a partial Brown-Sequard syndrome deserves mention. Kuroiwa and Araki (1963) reported autopsy findings in 3 patients with tonic seizures. They stressed the dominance of cervical cord lesions. As is usually the case in MS, however, there were also lesions at other levels of the central nervous system. We have recently seen a patient with a localized traumatic lesion of the cervical spinal cord who exhibited tonic seizures.
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Lhermitte's sign (Ekbom, 1971). We have been able to confirm Ekbom's observation in several cases. In paroxysmal hemiataxia and crossed paraesthesise (Cases 4 and 5) the attacks consisted of ataxia in the right arm and leg preceded by a sensation of heat and/or pain in the left side of the face and left arm. A transversely spreading activation of axons within a lesion in the upper part of the pons (fig. 2) may explain the crossed Brachlum conjunrtivum
'Q?
Lateral spinothalamic tract Med. lemnlscus Cortlcospinal and corticopontine tracts
Fro. 2.—Schematic drawing of transverse section of the pons, through motor trigeminal nucleus (according to standard textbooks of neuroanatomy).
distribution of ataxia and paraesthesiae. The ipsilateral ataxia may be explained by activation of fibres in the brachium conjunctivum. The contralateral sensation of heat and/or pain is thought to be caused by activation offibresin the ventral central trigeminal tract and in the dorsomedial part of the lateral spinothalamic tract In the pons the fibres in the lateral spinothalamic tract are segmentally arranged. Fibres conveying sensations of pain and temperature from the cervical segments are located dorsomedially in the lateral spinothalamic tract where they come in close contact with the ventral central trigeminal tract (Marburg, 1911; Wallenberg, 1911). A localized lesion within this area in the pons can, therefore, produce analgesia and thermal anaesthesia in one half of the face and in the shoulder and arm on the same side (Wallenberg, 1901; Bergmark, 1916; Foerster, 1927). The following case report shows that a single lesion in the pons can produce hemiataxia and crossed sensory disturbances with the same distribution as that seen in our 2 cases with paroxysmal hemiataxia and crossed paraesthesiae. Case 10.—A 44-year-old man with unremarkable past history. One morning he suddenly started sneezing and vertigo, double vision and walking difficulties developed within a few seconds. He also complained of a "pricking" sensation in the right half of the face and in the right arm. Neurological examination disclosed ataxia in the left arm and leg, altered sensibility in the right half of the face and in the right arm, dysarthria, left-sided palsy of the abducens nerve, skew deviation and nystagmus. The spinal fluid was normal. A four-vessel angiography revealed slight stenosis of the left vertebral artery at its origin from the subclavian artery.
The notion that an irritative lesion affecting a sensory path somewhere in the central nervous system can give rise to paraesthesiae or pain is generally accepted. Our new suggestion is that an irritative lesion affecting a fibre tract involved in
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So"
Ventr. spinocerebell. tr Motor nucl., N. V Sensory nucl., N. V Y Ventr. central trigeminal tract
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central motor control, for instance, the brachium conjunctivum, can produce ataxia. We thus propose that ataxia can be produced by hyperactivity as well as by hypoactivity in a path subserving motor control. It can readily be shown that ataxia, of a cerebellar type, can be produced by bombardment of central structures with excess impulses in proprioceptive paths.
In paroxysmal dysarthria and ataxia it is difficult to suggest an exact localization of the responsible lesion. However, there are no anatomical obstacles to the "ephaptic theory." Several localizations of an irritative lesion are possible, for instance, the decussation of the brachia conjunctiva. Paroxysmal diplopia could be explained, for instance, by discharges in abducens nerve fibres within the pons, or by discharges in the medial longitudinal fasciculus. In one of our patients we observed spasm of the left medial rectus muscle during some attacks, and skew deviation with vertical diplopia during other attacks. In this case discharges in the medial longitudinal fasciculus could explain the observed phenomena. Paroxysmal akinesia could possibly be explained by excessive discharges within an inhibitory path, subserving regulation of muscular tone. Paroxysmal numbness and pain are, obviously, readily accounted for by the ephaptic theory. Regarding our single case of paroxysmal itching it is difficult to explain why the subjective sensation was itch and not pain. An abundance of evidence exists to indicate that itching is closely related to cutaneous pain. The fibres conducting the quality of itching seem to be the same as, or at least closely following those which convey the sense of pain (Sweet, 1959). Torebjork (1974) recorded C-fibre activity with micro-electrodes from intact sensory fascicles in the human peroneal nerve. He found that sensations produced by cutaneous stimuli inducing intense afferent C-fibre activity were reported as "burning, or delayed, pain," whereas stimuli eliciting low frequency activity were often reported as "itch or burning itch." It is therefore possible that paroxysmal itching and paroxysmal pain are elicited from irritative lesions in the same fibre paths—differences in impulse patterns determining whether the sensation will be one of itch or of pain. SUMMARY
Twenty-two out of 235 patients with undoubted or suspected MS, treated at the Neurological Clinic, Uppsala, during the eight-year period, 1966-1973, had paroxysmal symptoms during the course of their disease. Paroxysmal dysarthria and ataxia (7 cases), and tonic seizures (5 cases) were the most common types of attacks. Some types of attacks (paroxysmal hemiataxia and crossed parssthesia;, paroxysmal itching, diplopia as the single paroxysmal symptom) do not seem to have been described previously. A patient with tonic seizures caused by a localized, traumatic lesion of the cervical spinal cord is also described.
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Vibration is known to be an efficient stimulus for intramuscular stretch receptors (Hagbarth, 1973). An electromechanical vibrator (stimulus amplitude 2-2 mm; frequency 130 Hz) was applied to the forearm of 5 normal adult subjects. In thefinger-to-nosetest an ataxia of cerebellar type was clearly seen in the vibrated arm during the first few trials. On further repetition of the manoeuvre the subjects were able to compensate for the abnormal influx of impulses.
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It is suggested that the paroxysmal phenomena in MS are caused by a transversely spreading ephaptic activation of axons within a partially demyelinated lesion in fibre tracts somewhere in the central nervous system. The different paroxysmal phenomena are discussed in the light of this hypothesis.
ANDERMANN, F., COSGROVE, J. B. R., LLOYD-SMITH, D., and WALTERS, A. M. (1959) Paroxysmal
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