Brain (1990), 113, 709-720
A QUANTITATIVE STUDY OF SENSORY FUNCTION IN HEREDITARY SPASTIC PARAPLEGIA by w.
SCHADY and
A. SHEARD
(From the Department of Neurology, Manchester Royal Infirmary, Manchester, UK) SUMMARY Somatic sensation was studied in 23 patients from 14 families with hereditary spastic paraplegia. Quantitative sensory testing revealed significantly raised thermal, heat pain, vibratory and tactile thresholds in patients as compared with normal controls. Cutaneous sensitivity was more severely impaired in the feet than in the hands. All patients had at least one elevated sensory threshold. Sensory nerve conduction studies were abnormal in 6 patients, 5 of whom were members of the same family. Somatosensory evoked potentials were reduced on average to half the size of those of controls. Although the clinical picture is dominated by a spastic paraparesis, subclinical sensory impairment is common in hereditary spastic paraplegia and may reflect involvement of peripheral nerves, afferent pathways in the spinal cord or both.
INTRODUCTION
Hereditary spastic paraplegia occupies a relatively unique position within the inherited neural degenerations on account of the homogeneity of its clinical picture. While associations with optic atrophy, extrapyramidal signs, amyotrophy and cerebellar ataxia have been described, these are rare. In most cases spasticity and moderate weakness of the lower limbs are the only manifestations of the disease. Reference to a sensory deficit has been made in several reports (Bickerstaff, 1950; Behan and Maia, 1974; Harding, 1981; Boustany et al., 1987), but its extent has not been quantified. We have studied the incidence and severity of sensory impairment in patients with hereditary spastic paraplegia by psychophysical and neurophysiological methods. Our results show that sensory disturbance, though usually mild, is a common accompaniment of the disease. MATERIAL AND METHODS Patients Twenty-three patients from 14 kinships with hereditary spastic paraplegia (HSP) were studied. The diagnosis was based on the presence of a well-documented family history and gradually progressive evolution. No sporadic cases were accepted for study. The clinical picture was dominated by a spastic paraparesis in all patients. Twelve patients were male and 11 were female. Their ages ranged from 20 to 73 (mean 45) yrs. Details are given in Table 1. Each patient's disability at the time of testing was scored in accordance with the following criteria (Behan and Maia, 1974): 1, minimal or no symptoms; 2, stiff gait but no help required to walk; 3, gait possible only with the aid of sticks or walking frame; 4, patient confined, Correspondence to: Dr W. Schady, Department of Neurology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. © Oxford University Press 1990
W. SCHADY AND A. SHEARD
710
CLINICAL AND GENETIC DETAILS IN 23 PATIENTS WITH HEREDITARY SPASTIC PARAPLEGIA
TABLE Age (yrs) 60 32
Sex M M
Kinship 1 1
F M F M F M F F F F F F F M M F M M
2 2 3 3 4 4 4 4
12 13 14 15 16 17 18 19 20
26 25 58 35 41 49 47 43 38 61 57 34 73 36 20 56 65 48
21 22
27 55
23
41
uient 1 2 3 4
5 6 7 8 9 10 11
Age at onset (yrs) 43 20
Severity of paraparcsis 3 2
2 1 2 14 11 18
2 2 2 2 4 3
8
4
4 2 3 3 2 3 2
11
11 7 40 30 32 61 27 9 6 7 18
M M
12 13
13 40
2 3
M
14
35
2
4
5 6 7 7 7 8 9 10
Additional features Deafness, sensory loss, wasted EDB
Sensory loss Sensory loss Sensory loss
1
2 3 2
UL amyotrophy Sensory loss, wasted EDB Optic atrophy Sensory loss, wasted EDB Sensory loss
UL = upper limb, EDB = extensor digitorum brevis muscle. For details of sensory loss, see text.
for practical purposes, to chair or bed. All patients gave informed consent in accordance with the Declaration of Helsinki. Quantitative sensory examination In all cases a detailed neurological examination was performed. This was followed by quantitative testing for temperature, pain, vibration and tactile sensory thresholds in the right hand and foot. Thermal sensibility was tested by the Marstock method (Fruhstorfer « al., 1976). The thermode employed has a stimulating surface of 2.5x5 cm which operates on the Peltier principle and can either be warmed or cooled. The temperature, measured by a thermocouple fixed to the stimulating surface, is displayed digitally and is recorded by a pen recorder. Having applied the stimulator to the skin, it was warmed at a rate of 1.0° C/s (1.5-2° C/s in the foot), starting from a baseline temperature of 31 ° C, until the subject first perceived warmth. At this point he pressed a switch which reversed the current and cooled the stimulator. When a sensation of cold was first felt, he again pressed the switch to reverse the current, thereby commencing a new cycle; 8 - 1 0 cycles were recorded at each site and a warm-cold threshold difference (warm-cold limen) was calculated from the latter, stable part of the recording (fig. 1). A warm-cold lirnen was obtained in all patients at 2 sites, namely the hypothenar eminence and the lateral aspect of the foot just below the malleolus. A weight of 240 g was placed on the upper surface of the thermode to standardize the pressure of application and obtain good contact between skin and thermode. Care was taken to ensure that the skin temperature at the onset of the procedure was 33 ± 1 ° C for the hand and 32 ± 1 ° C for the foot. The ambient temperature was 24—26° C.
HEREDITARY SPASTIC PARAPLEGIA
711
50-|
HPT 4642U so u
Q
34WCL 30-
26-1
Hand
Foot
FIG. 1 Representative record of thermal (warm-cold limen, WCL) and heat pain thresholds (HPT) in the hand (left traces) and in the foot (nght traces). Note rise in thresholds over the first few trials until values stabilize.
Heat pain thresholds were determined with the same equipment at the same sites on the hand and foot. The stimulating thermode was warmed at 3° C/s and the subject was instructed to press the switch when he first felt pain. The temperature was then allowed to return to baseline for 10—15 s in order to avoid nociceptor sensitization. The procedure was repeated 4 times and the mean of the last 3 values was calculated. Vibration thresholds were obtained by means of a Vibrameter (Somedic AB), which delivers a 100 Hz sine wave through a hand-held probe. The amplitude of the sine wave was slowly increased by the operator while the displacement of the probe (in /im) was read off a continuous digital display. A pressure monitor ensured that the probe was applied with a constant force. The vibration threshold (VT) was defined as the midpoint between vibration perception and disappearance thresholds. Measurements were undertaken on the dorsum of the hand over the first metacarpaJ bone, on the lateral malleolus and in the area of the foot overlying the fifth metatarsal bone. At least 3 values were obtained at each site, from which a mean VT was derived. A standard set of graded von Frey hairs was employed to assess tactile sensibility on the pulp of the index and little fingers, the hypothenar region, the lateral aspect of the foot and the pulp of the big toe. The threshold (in millinewtons, mN) was regarded as the force required to obtain a correct response in 3 out of 4 trials. Two-point discrimination was measured on the pulp of the index and little fingers and in the hypothenar region by means of calipers with blunt points and a mm scale showing the distance between the points. Electrophysiological investigation Nerve conduction studies were performed in 22 patients with standard techniques using a Medelec MS6 EMG system. Sensory action potentials were obtained from the right median, ulnar, superficial peroneal and sural nerves, and motor conduction velocities from the right median, ulnar, common peroneal and tibial nerves. If an abnormality was detected, the same studies were undertaken on the left side. Limb temperature was maintained at 32—34° C by means of a thermostatically-controlled infrared heat source. Somatosensory evoked potentials were obtained bilaterally with a Cadwell 7400 4-channel recorder. The median (19 patients) and tibial (11 patients) nerves were stimulated through surface electrodes placed at the wrist and ankle, respectively. The stimulus was a rectangular electric pulse of 0.1 ms duration delivered at 5 Hz and at an intensity 25% above threshold for a visible motor twitch. During median nerve stimulation,
712
W. SCHADY AND A. SHEARD
responses were recorded at Erb's point (N9), the seventh cervical vertebra (N13) and a point on the scalp 2.5 cm behind Cz, 7 cm lateral to the midline on the contralateral side (N20). When stimulating the tibial nerve, cortical responses were obtained from the midline, 2.5 cm posterior to Cz. To ensure reproducibility 200 responses were averaged twice on each side. Analysis of data Results were compared with those from 124 controls of both sexes, aged 20—79 yrs, who were either healthy paramedical staff or hospital patients with nonneurological disease. Since sensory thresholds are known to increase with age (Dyck et al., 1984; Kenshalo, 1986; Mitchell and Schady, 1988), control values were plotted against age and the 95% confidence limits of the regression line were calculated. Patients' thresholds were considered abnormal if they fell outside this range.
RESULTS
Genetic aspects Inheritance was clearly autosomal dominant in 11 families, where there were affected members of both sexes in two or more generations. In kinships 2, 4 and 12, siblings were affected but there was no history of either parent having had the disease. The parents, however, were not examined. Although affected siblings may be taken as evidence of autosomal recessive inheritance, there was no parental consanguinity and autosomal dominant inheritance cannot be excluded in these families, since dominant disorders may vary in clinical expression. The age of onset was uniformly under 20 yrs in 8 families. In the remaining 6 families the age of onset varied from 20 to 61 yrs for different family members. Using Harding's (1981) classification, 9 families were of type I (age of onset below 35 yrs), none were of type II (age of onset uniformly above 35 yrs) and 4 were mixed. In our material, therefore, a cut-off point of 20 yrs led to less overlap between families with the juvenile and adult-onset forms of hereditary spastic paraplegia than using Harding's criterion. Clinical examination All patients had markedly increased lower limb tone, exaggerated knee and ankle jerks and extensor plantar responses, although the severity of the syndrome varied. By disability, 3 patients had a score of 4, 7 scored 3, 12 scored 2 and 1 patient scored 1 (see Methods). Patients with adult-onset HSP had a similar mean disability score of 2.55 to those with juvenile onset (2.57). However, a striking difference became apparent when patients' scores were divided by the duration of disease in years. The relative disability score for patients with type I HSP was 0.082±0.032, that for patients with type II HSP 0.194±0.103 (P < 0.001). These results indicate that patients in the adult-onset group reached a given level of disability twice as fast as their juvenile-onset counterparts. Fifteen patients had brisk upper limb reflexes without weakness. One patient (Case 19, Table 1) was unusual in that he showed prominent wasting of the muscles of his hands and forearms with depressed upper limb reflexes but no sensory loss or lower
HEREDITARY SPASTIC PARAPLEGIA
713
limb wasting. Another patient had perceptive deafness and a third had optic atrophy. Three patients had bilateral wasting of extensor digitorum brevis (EDB) muscles but not elsewhere. No patient had intellectual impairment, skin changes, retinal pigmentation or an extrapyramidal syndrome. Only 2 had frank pes cavus. Seven patients, 3 of them members of the same family, had evidence of sensory impairment on standard bedside examination (Table 1). Case 2 had a 'glove and stocking' pattern of sensory loss. Case 8 had absent vibration sense to the hips. Case 9 had mild impairment of joint position sense in the toes. Case 11 showed distally reduced pin prick perception in upper and lower limbs, absent vibration sense to the pelvis and impaired joint position sense in the feet. Case 20 had impaired pin prick and light touch perception to mid-leg level. Case 22 showed loss of vibration sense and joint position sense in the feet. Case 23 had noticed numbness of his toes and was found to have impairment of pain sensitivity in the right big toe and of vibration sense below the knees. Another patient complained of unpleasant burning or 'wet' feelings in her lower limbs but had a normal sensory examination. Nerve conduction studies Six patients, 5 of whom were members of the same family, had frankly reduced or absent sensory action potentials in upper and lower limbs (Table 2). Despite the reduced
WITH TABLE 2 NERVE (CONDUCTION STUDIES IN PATIENTS HEREDITARY SPASTIC PARAPLEGIA1
Case Median MCV Ulnar MCV Common peronea] MCV Tibial MCV Median SAP Ulnar SAP Superficial peroneal SAP Sural SAP
19 Abs. 43* 39 39 6* 6 4 4
2 37* 37* Abs. 1.5* — _
7 60 60 50 45 Abs. Abs. Abs. Abs.
8 58 58 44 43 4* 1.5* Abs. Abs.
9 60 72 46 2* 3* 3*
5
10
//
61 62 52 35* 5* 2* 3* 3
55 69 43 33* 1* 1* Abs Abs
1
Only patients with at least one abnormal value (indicated by an asterisk) are given. The last 5 patients are members of the same family. MCV = motor conduction velocity ( m s " ' ) ; SAP = sensory action potential (/iV); Abs. = absent.
amplitudes, there was no slowing of sensory conduction. These 6 patients were considered to have an electrophysiologically demonstrable peripheral neuropathy as well as corticospinal tract disease; 4 of them were among the 7 patients with sensory impairment on bedside examination. Motor conduction abnormalities were evident in only 3. Case 19 had impaired upper limb motor conduction and prominent electromyographic signs of denervation in forearm and hand muscles, although sensory conduction was only mildly affected. Compound muscle action potentials from EDB were reduced in 3 other patients in whom these muscles were wasted. Since motor and sensory conduction
714
W. SCHADY AND A. SHEARD
studies were otherwise normal, this isolated deficit may have been due to a local compression injury or to anterior horn cell loss and was not interpreted as a sign of poly neuropathy. In view of the electrophysiological evidence of peripheral nerve disease in all members of kinship 4, alternative diagnoses such as adrenoleukomyeloneuropathy were considered, but adrenal function tests in an affected male were normal (including plasma ACTH, cortisol, testosterone and gonadotrophin levels and ACTH stress test). Thermal and heat pain thresholds The thermal threshold in the hand (expressed as the warm-cold limen) was increased in 8 patients (35%). In the foot it was raised in 17 patients (74%), the increase being of greater magnitude than in the hand (fig. 2, upper panels). Thermal thresholds were not significantly different in patients with and without an electrophysiologically demonstrable peripheral neuropathy. Of the 7 patients with clinical sensory impairment, 4 had increased thermal thresholds in the hand and 5 in the foot. There was no relationship between thermal thresholds and duration or severity of the disease. All heat pain thresholds fell within the normal range. This is not surprising, bearing in mind that heating was not allowed to proceed beyond 50° C in order to avoid burning, and that the upper limit of normal exceeded that value for all decades. Since pain thresholds do not regress with age (Kenshalo, 1986) or do so only weakly (Mitchell and Schady, 1988), we compared heat pain thresholds in HSP patients as a group with those of controls. Values for the foot were 46.8 ±2.7° C (mean±SD) in patients and 44.5±3.2° C in controls (P < 0.01). Corresponding values in the hand were not significantly different. Vibratory and tactile thresholds Tactile thresholds in the index and little fingers and in the hypothenar eminence were normal in all patients. Two-point discrimination was impaired in the little finger in 3 patients and on the hypothenar eminence in 6. In the foot, tactile thresholds were elevated in 10 out of 20 patients, including 4 with a peripheral neuropathy, 3 of whom had been found to have sensory impairment in bedside testing (fig. 2, middle panels). Vibration thresholds in the hand were elevated in only 1 patient. In the foot, however, vibration thresholds were abnormally high in 13 out of 20 patients (65%), including all patients with an electrophysiologically demonstrable polyneuropathy (fig. 2, lower panels). Vibration thresholds were also obtained from the ankle with similar results; 53% of patients had elevated thresholds at this site. Ten out of 17 patients without neuropathy had impaired vibratory perception in the foot and/or at the ankle. There was no correlation between tactile or vibratory thresholds and duration of disease, age of onset, severity of disease or thermal thresholds. All patients had at least one abnormal sensory threshold. Since only 7 had clinical sensory impairment, it follows that an unsuspected sensory deficit was found in 70% of patients. Three or more raised thresholds were found in 13 patients, of whom 12
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FIG. 2. Warm-cold limen (WCL), tactile threshold (TT) and vibration threshold (VT) plotted against age (in yrs) in patients with hereditary spastic paraplegia. Left panels correspond to the hand, right panels to the foot. Filled circles represent patients with a peripheral neuropathy. The least squares regression line (broken) and upper 95% confidence limit (solid line) for 124 normal controls are also shown. Note log scale for the ordinate in the lower four panels.
had involvement of sensory submodalities mediated by both large fibres (touch, vibration) and small fibres (warm, cold). With a simplified protocol relying on the thermal and vibratory thresholds at a single site in the foot, 19 patients would have been found to have impaired sensibility. Somatosensory evoked potentials Somatosensory evoked potentials (SEPs) to median nerve stimulation could be obtained in 17 out of 19 patients. Both patients with absent SEPs also had reduced peripheral
716
W. SCHADY AND A. SHEARD
sensory action potentials. Three patients had a delayed N9 peak recorded over the brachial plexus, one had a prolonged N9-N13 interpeak latency difference and 2 had prolonged N13 —N20 interpeak latencies. In all these cases the delay was modest, amounting to less than 2 ms outside the normal range. After excluding patients with a neuropathy, the amplitude of subcortical SEPs, both at the brachial plexus and over the cervical cord, did not differ significantly from that of normal controls. However, the amplitude of cortical SEPs was significantly reduced. In 14 patients with normal peripheral sensory conduction, the mean N20 potential amplitude was 2.8 ±1.1 /iV, compared with 3.8±2.0 fiV in control subjects (P < 0.02). Somatosensory evoked responses to tibial nerve stimulation were recorded in 10 patients without evidence of peripheral neuropathy. In 1 case they were absent bilaterally, while in 4 cases they were absent unilaterally but could be obtained from the other side. The mean amplitude of the P40 potential, when recordable, was 2.4 ±0.8 fiV in patients and 5.3 ±2.1 pV in control subjects (P < 0.001). The latency of the P40 peak was normal in all cases. Fourteen patients (60%) had an abnormality of either nerve conduction studies, somatosensory evoked potentials or both. DISCUSSION
Hereditary spastic paraplegia (HSP) presents a relatively uniform clinical picture in the majority of patients. In the uncomplicated form there is insidiously progressive lower limb spasticity, with moderate weakness and no lower motor neuron features. The disease may be transmitted as an autosomal dominant or, less commonly, as an autosomal recessive trait. This distinction is not always easy, as dominant disorders may show variable clinical expression. A family in point is our kinship 4, where all of 6 siblings had the disease, and neither parent was known to have been affected. Either autosomal dominant or autosomal recessive inheritance is possible. Inheritance may have been recessive in 2 other families (kinships 2 and 12), but there was no consanguinity and the parents were not examined, so autosomal dominant transmission again cannot be excluded. Since only patients with a clear family history were admitted to the study, there may be an over-representation of dominantly inherited kinships in our material. Subdivision of patients is possible on the basis of age of onset of symptoms. In a study of 22 families, Harding (1981) divided dominant HSP into two forms, namely type I, with an age of onset below 35 yrs, and type II, with onset usually over 35 yrs. In our families, 20 yrs was a better cut-off point between juvenile and adult-onset forms of HSP. By this criterion, 8 families were uniformly of juvenile onset and 6 families were of adult onset. On average, within the limitations imposed by our rather crude disability scoring system, the latter progressed twice as rapidly as the former. Harding (1981) also found that late onset is associated with a worse prognosis. Families have been reported in which HSP is associated with optic atrophy, extrapyramidal disease, deafness, amyotrophy or cerebellar ataxia (for review, see Harding, 1984). Twenty of our 23 patients had the so-called 'pure' form of the disease. One patient had upper limb amyotrophy as well as a paraparesis, a previously recognized
HEREDITARY SPASTIC PARAPLEGIA
717
association (Silver, 1966). Another patient had perceptive deafness and a third had optic atrophy. In the presence of an otherwise typical clinical picture and a positive family history, their inclusion in the series was thought justified. Six patients had reduced or absent peripheral sensory action potentials, implying that they had a polyneuropathy as well as corticospinal tract disease. None of them was similar to previously described cases of hereditary spastic paraparesis with sensory neuropathy, who suffered from a progressive ulcerating sensory polyneuropathy which overshadowed the pyramidal syndrome (van Epps and Kerr, 1940; Khalifeh and Zellweger, 1963; Koenig and Spiro, 1970; Cavanagh et al., 1979). The clinical picture in our patients was also quite unlike that of families with peroneal muscular atrophy with pyramidal features (Harding and Thomas, 1984), in whom the neuropathy predominates. Adrenoleukomyeloneuropathy was considered in kinship 4 but was thought to be unlikely by the demonstration of normal adrenal function tests in a male member of the family. Other authors have reported impaired sensation in some patients with otherwise uncomplicated HSP. Bickerstaff (1950) found defective lower limb sensitivity to vibration in 7 out of 43 examined members of a large kinship with HSP. In no case was any superficial sensory loss discovered. In 52% of the cases reported by Behan and Maia (1974), 27% of those of Harding (1981) and 60% of those of Boustany et al. (1987) there was a sensory deficit in the lower limbs. It was restricted to vibration sense and, in a few patients, joint position sense. Seven of our patients had sensory impairment on bedside testing, predominantly involving dorsal column submodalities, as in previous reports, though 4 patients had reduced pin prick perception, which in 1 case extended to the upper limbs. Four of these 7 patients were among the group in whom nerve impairment studies showed a peripheral neuropathy. Quantitative sensory testing (QST) was more revealing than bedside examination of sensibility. Our results show that some sensory abnormality is almost universal in the lower extremities of patients with HSP if sensitive enough methods are applied to detect it. QST is often considered excessively cumbersome for routine use, but our battery of tests at several sites in the hand and foot usually took no more than 45 min to apply. It allowed us to test a range of sensory submodalities, an evident advantage in view of the variability inherent in any form of sensory testing and the lack of correlation between the various thresholds. With a simplified protocol, relying on results obtained at a single site in hand and foot, QST need be no more time-consuming than standard electrophysiological tests, and yet our findings suggest that in some instances it may be more sensitive. While only 60% of our patients had abnormal nerve conduction studies and/or somatosensory evoked potentials, all had one or more abnormal sensory thresholds. The methodology of QST requires further discussion. For the sake of simplicity we chose the method of limits for measurement of cutaneous thresholds. Forced-choice techniques are psychophysically superior, since they reduce response bias and eliminate variability in reaction times (Dyck et al., 1984; Jamal et al., 1985), but they also lengthen the procedure. This is particularly important when several sensory submodalities need to be tested, as distractability will increase with fatigue. For thermal thresholds, the intrasubject variability inherent in the 'Marstock' technique presents a serious problem
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W. SCHADY AND A. SHEARD
in longitudinal studies (Fagius and Wahren, 1981), but it should not invalidate the results of case control studies such as ours. The Marstock method has the added advantage of allowing measurement of pain thresholds (Fruhstorfer et al., 1976). With regard to vibration sense, the vibrameter that we employed has a pressure monitor which ensures that the probe is applied with a constant force, contrary to the standard biothesiometer which does not make allowances for variable damping of the vibratory stimulus (Goldberg and Lindblom, 1979). Lastly, we chose von Frey hairs to assess tactile sensitivity because, although they do not provide a fully controlled physical stimulus, they are cheap and produce a similar range of thresholds in fingers and toes to those obtained with more sophisticated techniques (Dyck et al., 1984). It should be emphasized that the methods used, and the testing sequence, were the same in patients and controls. The disturbance of cutaneous sensitivity detectable by QST affected all modalities. Most surprising was the increase in thermal thresholds in patients as compared with controls, especially in the lower limbs, where raised values were found in three-quarters of the patients. Heat pain thresholds in the foot were also increased, although less strikingly. This disturbance of 'spinothalamic' function applied regardless of whether patients with an electrophysiologically proven sensory polyneuropathy were excluded. There was no correlation between sensory thresholds and disease severity, disease duration or age of the patient. Our results, therefore, do not support the view expressed by some authors that sensory loss in HSP is increasingly common with advancing age (Schwarz and Liu, 1956; Behan and Maia, 1974). All previous reports of clinical sensory impairment in uncomplicated HSP refer to modalities mediated by large fibres. Our finding of abnormal vibratory and tactile thresholds was therefore less unexpected than the results of thermal testing. Although patients with a polyneuropathy had the highest thresholds, vibration perception was impaired in the foot or at the ankle in over half of those without a neuropathy. This suggests central nervous system dysfunction, a conclusion further supported by the SEP results. After excluding patients with abnormal peripheral conduction, the amplitude of cortical SEPs from the lower limbs was less than half that of healthy controls. Cortical SEPs from the upper limbs were also significantly reduced, though to a lesser extent. Abnormalities in somatosensory evoked potentials in HSP have previously been reported by other authors (Pedersen and Trojaborg, 1981; Thomas et al., 1981; Dimitrijevic et al., 1982). Neuropathological studies have shown dorsal column degeneration in some patients with HSP (Schwarz and Liu, 1956; Behan and Maia, 1974), in keeping with the neurophysiological evidence of posterior column dysfunction. By contrast, there are no reports of spinothalamic tract degeneration in HSP. Nonetheless, our data indicate that afferent pathways mediating pain and thermal sensibility are not spared. There are pointers to both peripheral and central nervous system disease. Six of our patients clearly had a neuropathy. The others might be argued to have had a small fibre neuropathy, since nerve conduction studies assess function in large myelinated fibres only. On the other hand, some of the highest thermal thresholds correspond to patients with normal peripheral conduction, suggesting spinothalamic tract involvement in some cases.
HEREDITARY SPASTIC PARAPLEGIA
719
Whatever the precise site of damage, the disease may extend to the upper limbs in a few patients, as evidenced by abnormal sensory thresholds or exaggerated tendon reflexes. It is interesting that 5 out of the 6 patients with a neuropathy were members of the same family. This may explain why the proportion of patients with neuropathy in our series is greater than that of previous authors. A number of reports of HSP with normal peripheral nerve function concern single families (Holmes and Shaywitz, 1977; Dimitrijevic et al., 1982) or only 3 families in the study by McLeod et al. (1977). If neuropathy does not occur randomly in HSP but within genetically distinct subgroups, it is unlikely to be recognized unless large numbers of families are studied. We wish to emphasize, however, that even in the absence of a polyneuropathy sensory impairment is common in HSP, pointing to the kind of multisystem involvement that is associated with most familial nervous system degenerations. ACKNOWLEDGEMENTS We wish to thank Drs R. G. Lascelles, D. Neary, M. Sambrook and D. I. Shepherd for referring patients. Our thanks also to Professor U. Lindblom and Dr A. E. Harding for reviewing the manuscript, to Ms L. Hunt for assistance with statistical analysis, and to Dr D. Donnai for advice on genetic aspects. REFERENCES BEHAN WMH, MAIA M (1974) StrumpeH's familial spastic paraplegia: genetics and neuropathology. Journal of Neurology, Neurosurgery and Psychiatry, 37, 8 — 20. BICKERSTAFF ER (1950) Hereditary spastic paraplegia. Journal of Neurology, Neurosurgery and Psychiatry, 13, 134-145. BOUSTANY R-MN, FLEISCHNICK E, ALPER CA, MARAZITA ML, SPENCE MA, MARTIN JB, KOLODNY EH
(1987) The autosomal dominant form of 'pure' familial spastic paraplegia: clinical findings and linkage analysis of a large pedigree. Neurology, Cleveland, 37, 910—915. CAVANAGH NPC, EAMES RA, GALVIN RJ, BRETT EM, KELLY RE (1979) Hereditary sensory neuropathy
with spastic paraplegia. Brain, 102, 79—94. DIMITRIJEVIC MR, LENMAN JAR, PREVEC T, WHEATLY K (1982) A study of posterior column function
in familial spastic paraplegia. Journal of Neurology, Neurosurgery and Psychiatry, 45, 46—49. DYCK PJ, KARNES J, O'BRIEN PC, ZIMMERMAN IR (1984) Detection thresholds of cutaneous sensation
in humans. In: Peripheral Neuropathy, Volume 1. Second edition. Edited by P. J. Dyck, P. K. Thomas, E. H. Lambert and R. Bunge. Philadelphia and London: W. B. Saunders, pp. 1103-1138. FAGIUS J, WAHREN LK (1981) Variability of sensory threshold determination in clinical use. Journal of the Neurological Sciences, 51, 11—27. FRUHSTORFER H, LINDBLOM U, SCHMIDT WG (1976) Method for quantitative estimation of thermal thresholds in patients. Journal of Neurology, Neurosurgery and Psychiatry, 39, 1071 — 1075. GOLDBERG JM, LINDBLOM U (1979) Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. Journal of Neurology, Neurosurgery and Psychiatry, 42, 793-803. HARDING AE (1981) Hereditary 'pure' spastic paraplegia: a clinical and genetic study of 22 families. Journal of Neurology, Neurosurgery and Psychiatry, 44, 871—883. HARDING AE (1984) The Hereditary Ataxias and Related Disorders. Edinburgh: Churchill Livingstone, pp. 174-204. HARDING AE, THOMAS PK (1984) Peroneal muscular atrophy with pyramidal features. Journal ofNeurology, Neurosurgery and Psychiatry, 47, 168—172.
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HOLMES GL, SHAYWITZ BA (1977) Strumpell's pure familial spastic paraplegia: case study and review of the literature. Journal of Neurology, Neurosurgery and Psychiatry, 40, 1003—1008. JAMAL GA, HANSEN S, WEIR A!, BALLANTYNE JP (1985) An improved automated method for the
measurement of thermal thresholds. 1. Normal subjects. Journal of Neurology, Neurosurgery and Psychiatry, 48, 354-360. KENSHALO DR (1986) Somesthetic sensitivity in young and elderly humans. Journal of Gerontology, 41, 732-742. KHAUFEH RR, ZELLWEGER H (1963) Hereditary sensory neuropathy with spinal cord disease. Neurology,
Minneapolis, 13, 405-411. KOENIG RH, SPIRO AJ (1970) Hereditary spastic paraparesis with sensory neuropathy. Developmental Medicine and Child Neurology, 12, 576—581. MCLEOD JG, MORGAN JA, REYE C (1977) Electrophysiological studies in familial spastic paraplegia. Journal of Neurology, Neurosurgery and Psychiatry, 40, 611—615. MITCHELL S, SCHADY W (1988) Somatic sensation in the elderly. In: Peripheral Nerve Changes in the Elderly. Edited by P. K. Thomas. Chichester: John Wiley, pp. 157-164. PEDERSEN L, TROJABORG W (1981) Visual, auditory and somatosensory pathway involvement in hereditary cerebellar ataxia, Friedreich's ataxia and familial spastic paraplegia. Electroencephalography and Clinical Neurophysiology, 52, 283-297. SCHWARZ GA, Liu C-N (1956) Hereditary (familial) spastic paraplegia: further clinical and pathologic observations. Archives of Neurology and Psychiatry, Chicago, 75, 144—162. SILVER JR (1966) Familial spastic paraplegia with amyotrophy of the hands. Journal of Neurology, Neurosurgery and Psychiatry, 29, 135 — 144. THOMAS PK, JEFFERYS JGR, SMITH IS, LOULAKAKIS D (1981) Spinal somatosensory evoked potentials
in hereditary spastic paraplegia. Journal of Neurology, Neurosurgery and Psychiatry, 44, 243—246. VAN EPPS C, KERR HD (1940) Familial lumbosacral syringomyelia. Radiology, 35, 160-173. (Received August 19, 1988. Revised June 14, 1989. Accepted July 3, 1989)
A QUANTITATIVE STUDY OF SENSORY FUNCTION IN HEREDITARY SPASTIC PARAPLEGIA by w.
SCHADY and
A. SHEARD
(From the Department of Neurology, Manchester Royal Infirmary, Manchester, UK) SUMMARY Somatic sensation was studied in 23 patients from 14 families with hereditary spastic paraplegia. Quantitative sensory testing revealed significantly raised thermal, heat pain, vibratory and tactile thresholds in patients as compared with normal controls. Cutaneous sensitivity was more severely impaired in the feet than in the hands. All patients had at least one elevated sensory threshold. Sensory nerve conduction studies were abnormal in 6 patients, 5 of whom were members of the same family. Somatosensory evoked potentials were reduced on average to half the size of those of controls. Although the clinical picture is dominated by a spastic paraparesis, subclinical sensory impairment is common in hereditary spastic paraplegia and may reflect involvement of peripheral nerves, afferent pathways in the spinal cord or both.
INTRODUCTION
Hereditary spastic paraplegia occupies a relatively unique position within the inherited neural degenerations on account of the homogeneity of its clinical picture. While associations with optic atrophy, extrapyramidal signs, amyotrophy and cerebellar ataxia have been described, these are rare. In most cases spasticity and moderate weakness of the lower limbs are the only manifestations of the disease. Reference to a sensory deficit has been made in several reports (Bickerstaff, 1950; Behan and Maia, 1974; Harding, 1981; Boustany et al., 1987), but its extent has not been quantified. We have studied the incidence and severity of sensory impairment in patients with hereditary spastic paraplegia by psychophysical and neurophysiological methods. Our results show that sensory disturbance, though usually mild, is a common accompaniment of the disease. MATERIAL AND METHODS Patients Twenty-three patients from 14 kinships with hereditary spastic paraplegia (HSP) were studied. The diagnosis was based on the presence of a well-documented family history and gradually progressive evolution. No sporadic cases were accepted for study. The clinical picture was dominated by a spastic paraparesis in all patients. Twelve patients were male and 11 were female. Their ages ranged from 20 to 73 (mean 45) yrs. Details are given in Table 1. Each patient's disability at the time of testing was scored in accordance with the following criteria (Behan and Maia, 1974): 1, minimal or no symptoms; 2, stiff gait but no help required to walk; 3, gait possible only with the aid of sticks or walking frame; 4, patient confined, Correspondence to: Dr W. Schady, Department of Neurology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. © Oxford University Press 1990
W. SCHADY AND A. SHEARD
710
CLINICAL AND GENETIC DETAILS IN 23 PATIENTS WITH HEREDITARY SPASTIC PARAPLEGIA
TABLE Age (yrs) 60 32
Sex M M
Kinship 1 1
F M F M F M F F F F F F F M M F M M
2 2 3 3 4 4 4 4
12 13 14 15 16 17 18 19 20
26 25 58 35 41 49 47 43 38 61 57 34 73 36 20 56 65 48
21 22
27 55
23
41
uient 1 2 3 4
5 6 7 8 9 10 11
Age at onset (yrs) 43 20
Severity of paraparcsis 3 2
2 1 2 14 11 18
2 2 2 2 4 3
8
4
4 2 3 3 2 3 2
11
11 7 40 30 32 61 27 9 6 7 18
M M
12 13
13 40
2 3
M
14
35
2
4
5 6 7 7 7 8 9 10
Additional features Deafness, sensory loss, wasted EDB
Sensory loss Sensory loss Sensory loss
1
2 3 2
UL amyotrophy Sensory loss, wasted EDB Optic atrophy Sensory loss, wasted EDB Sensory loss
UL = upper limb, EDB = extensor digitorum brevis muscle. For details of sensory loss, see text.
for practical purposes, to chair or bed. All patients gave informed consent in accordance with the Declaration of Helsinki. Quantitative sensory examination In all cases a detailed neurological examination was performed. This was followed by quantitative testing for temperature, pain, vibration and tactile sensory thresholds in the right hand and foot. Thermal sensibility was tested by the Marstock method (Fruhstorfer « al., 1976). The thermode employed has a stimulating surface of 2.5x5 cm which operates on the Peltier principle and can either be warmed or cooled. The temperature, measured by a thermocouple fixed to the stimulating surface, is displayed digitally and is recorded by a pen recorder. Having applied the stimulator to the skin, it was warmed at a rate of 1.0° C/s (1.5-2° C/s in the foot), starting from a baseline temperature of 31 ° C, until the subject first perceived warmth. At this point he pressed a switch which reversed the current and cooled the stimulator. When a sensation of cold was first felt, he again pressed the switch to reverse the current, thereby commencing a new cycle; 8 - 1 0 cycles were recorded at each site and a warm-cold threshold difference (warm-cold limen) was calculated from the latter, stable part of the recording (fig. 1). A warm-cold lirnen was obtained in all patients at 2 sites, namely the hypothenar eminence and the lateral aspect of the foot just below the malleolus. A weight of 240 g was placed on the upper surface of the thermode to standardize the pressure of application and obtain good contact between skin and thermode. Care was taken to ensure that the skin temperature at the onset of the procedure was 33 ± 1 ° C for the hand and 32 ± 1 ° C for the foot. The ambient temperature was 24—26° C.
HEREDITARY SPASTIC PARAPLEGIA
711
50-|
HPT 4642U so u
Q
34WCL 30-
26-1
Hand
Foot
FIG. 1 Representative record of thermal (warm-cold limen, WCL) and heat pain thresholds (HPT) in the hand (left traces) and in the foot (nght traces). Note rise in thresholds over the first few trials until values stabilize.
Heat pain thresholds were determined with the same equipment at the same sites on the hand and foot. The stimulating thermode was warmed at 3° C/s and the subject was instructed to press the switch when he first felt pain. The temperature was then allowed to return to baseline for 10—15 s in order to avoid nociceptor sensitization. The procedure was repeated 4 times and the mean of the last 3 values was calculated. Vibration thresholds were obtained by means of a Vibrameter (Somedic AB), which delivers a 100 Hz sine wave through a hand-held probe. The amplitude of the sine wave was slowly increased by the operator while the displacement of the probe (in /im) was read off a continuous digital display. A pressure monitor ensured that the probe was applied with a constant force. The vibration threshold (VT) was defined as the midpoint between vibration perception and disappearance thresholds. Measurements were undertaken on the dorsum of the hand over the first metacarpaJ bone, on the lateral malleolus and in the area of the foot overlying the fifth metatarsal bone. At least 3 values were obtained at each site, from which a mean VT was derived. A standard set of graded von Frey hairs was employed to assess tactile sensibility on the pulp of the index and little fingers, the hypothenar region, the lateral aspect of the foot and the pulp of the big toe. The threshold (in millinewtons, mN) was regarded as the force required to obtain a correct response in 3 out of 4 trials. Two-point discrimination was measured on the pulp of the index and little fingers and in the hypothenar region by means of calipers with blunt points and a mm scale showing the distance between the points. Electrophysiological investigation Nerve conduction studies were performed in 22 patients with standard techniques using a Medelec MS6 EMG system. Sensory action potentials were obtained from the right median, ulnar, superficial peroneal and sural nerves, and motor conduction velocities from the right median, ulnar, common peroneal and tibial nerves. If an abnormality was detected, the same studies were undertaken on the left side. Limb temperature was maintained at 32—34° C by means of a thermostatically-controlled infrared heat source. Somatosensory evoked potentials were obtained bilaterally with a Cadwell 7400 4-channel recorder. The median (19 patients) and tibial (11 patients) nerves were stimulated through surface electrodes placed at the wrist and ankle, respectively. The stimulus was a rectangular electric pulse of 0.1 ms duration delivered at 5 Hz and at an intensity 25% above threshold for a visible motor twitch. During median nerve stimulation,
712
W. SCHADY AND A. SHEARD
responses were recorded at Erb's point (N9), the seventh cervical vertebra (N13) and a point on the scalp 2.5 cm behind Cz, 7 cm lateral to the midline on the contralateral side (N20). When stimulating the tibial nerve, cortical responses were obtained from the midline, 2.5 cm posterior to Cz. To ensure reproducibility 200 responses were averaged twice on each side. Analysis of data Results were compared with those from 124 controls of both sexes, aged 20—79 yrs, who were either healthy paramedical staff or hospital patients with nonneurological disease. Since sensory thresholds are known to increase with age (Dyck et al., 1984; Kenshalo, 1986; Mitchell and Schady, 1988), control values were plotted against age and the 95% confidence limits of the regression line were calculated. Patients' thresholds were considered abnormal if they fell outside this range.
RESULTS
Genetic aspects Inheritance was clearly autosomal dominant in 11 families, where there were affected members of both sexes in two or more generations. In kinships 2, 4 and 12, siblings were affected but there was no history of either parent having had the disease. The parents, however, were not examined. Although affected siblings may be taken as evidence of autosomal recessive inheritance, there was no parental consanguinity and autosomal dominant inheritance cannot be excluded in these families, since dominant disorders may vary in clinical expression. The age of onset was uniformly under 20 yrs in 8 families. In the remaining 6 families the age of onset varied from 20 to 61 yrs for different family members. Using Harding's (1981) classification, 9 families were of type I (age of onset below 35 yrs), none were of type II (age of onset uniformly above 35 yrs) and 4 were mixed. In our material, therefore, a cut-off point of 20 yrs led to less overlap between families with the juvenile and adult-onset forms of hereditary spastic paraplegia than using Harding's criterion. Clinical examination All patients had markedly increased lower limb tone, exaggerated knee and ankle jerks and extensor plantar responses, although the severity of the syndrome varied. By disability, 3 patients had a score of 4, 7 scored 3, 12 scored 2 and 1 patient scored 1 (see Methods). Patients with adult-onset HSP had a similar mean disability score of 2.55 to those with juvenile onset (2.57). However, a striking difference became apparent when patients' scores were divided by the duration of disease in years. The relative disability score for patients with type I HSP was 0.082±0.032, that for patients with type II HSP 0.194±0.103 (P < 0.001). These results indicate that patients in the adult-onset group reached a given level of disability twice as fast as their juvenile-onset counterparts. Fifteen patients had brisk upper limb reflexes without weakness. One patient (Case 19, Table 1) was unusual in that he showed prominent wasting of the muscles of his hands and forearms with depressed upper limb reflexes but no sensory loss or lower
HEREDITARY SPASTIC PARAPLEGIA
713
limb wasting. Another patient had perceptive deafness and a third had optic atrophy. Three patients had bilateral wasting of extensor digitorum brevis (EDB) muscles but not elsewhere. No patient had intellectual impairment, skin changes, retinal pigmentation or an extrapyramidal syndrome. Only 2 had frank pes cavus. Seven patients, 3 of them members of the same family, had evidence of sensory impairment on standard bedside examination (Table 1). Case 2 had a 'glove and stocking' pattern of sensory loss. Case 8 had absent vibration sense to the hips. Case 9 had mild impairment of joint position sense in the toes. Case 11 showed distally reduced pin prick perception in upper and lower limbs, absent vibration sense to the pelvis and impaired joint position sense in the feet. Case 20 had impaired pin prick and light touch perception to mid-leg level. Case 22 showed loss of vibration sense and joint position sense in the feet. Case 23 had noticed numbness of his toes and was found to have impairment of pain sensitivity in the right big toe and of vibration sense below the knees. Another patient complained of unpleasant burning or 'wet' feelings in her lower limbs but had a normal sensory examination. Nerve conduction studies Six patients, 5 of whom were members of the same family, had frankly reduced or absent sensory action potentials in upper and lower limbs (Table 2). Despite the reduced
WITH TABLE 2 NERVE (CONDUCTION STUDIES IN PATIENTS HEREDITARY SPASTIC PARAPLEGIA1
Case Median MCV Ulnar MCV Common peronea] MCV Tibial MCV Median SAP Ulnar SAP Superficial peroneal SAP Sural SAP
19 Abs. 43* 39 39 6* 6 4 4
2 37* 37* Abs. 1.5* — _
7 60 60 50 45 Abs. Abs. Abs. Abs.
8 58 58 44 43 4* 1.5* Abs. Abs.
9 60 72 46 2* 3* 3*
5
10
//
61 62 52 35* 5* 2* 3* 3
55 69 43 33* 1* 1* Abs Abs
1
Only patients with at least one abnormal value (indicated by an asterisk) are given. The last 5 patients are members of the same family. MCV = motor conduction velocity ( m s " ' ) ; SAP = sensory action potential (/iV); Abs. = absent.
amplitudes, there was no slowing of sensory conduction. These 6 patients were considered to have an electrophysiologically demonstrable peripheral neuropathy as well as corticospinal tract disease; 4 of them were among the 7 patients with sensory impairment on bedside examination. Motor conduction abnormalities were evident in only 3. Case 19 had impaired upper limb motor conduction and prominent electromyographic signs of denervation in forearm and hand muscles, although sensory conduction was only mildly affected. Compound muscle action potentials from EDB were reduced in 3 other patients in whom these muscles were wasted. Since motor and sensory conduction
714
W. SCHADY AND A. SHEARD
studies were otherwise normal, this isolated deficit may have been due to a local compression injury or to anterior horn cell loss and was not interpreted as a sign of poly neuropathy. In view of the electrophysiological evidence of peripheral nerve disease in all members of kinship 4, alternative diagnoses such as adrenoleukomyeloneuropathy were considered, but adrenal function tests in an affected male were normal (including plasma ACTH, cortisol, testosterone and gonadotrophin levels and ACTH stress test). Thermal and heat pain thresholds The thermal threshold in the hand (expressed as the warm-cold limen) was increased in 8 patients (35%). In the foot it was raised in 17 patients (74%), the increase being of greater magnitude than in the hand (fig. 2, upper panels). Thermal thresholds were not significantly different in patients with and without an electrophysiologically demonstrable peripheral neuropathy. Of the 7 patients with clinical sensory impairment, 4 had increased thermal thresholds in the hand and 5 in the foot. There was no relationship between thermal thresholds and duration or severity of the disease. All heat pain thresholds fell within the normal range. This is not surprising, bearing in mind that heating was not allowed to proceed beyond 50° C in order to avoid burning, and that the upper limit of normal exceeded that value for all decades. Since pain thresholds do not regress with age (Kenshalo, 1986) or do so only weakly (Mitchell and Schady, 1988), we compared heat pain thresholds in HSP patients as a group with those of controls. Values for the foot were 46.8 ±2.7° C (mean±SD) in patients and 44.5±3.2° C in controls (P < 0.01). Corresponding values in the hand were not significantly different. Vibratory and tactile thresholds Tactile thresholds in the index and little fingers and in the hypothenar eminence were normal in all patients. Two-point discrimination was impaired in the little finger in 3 patients and on the hypothenar eminence in 6. In the foot, tactile thresholds were elevated in 10 out of 20 patients, including 4 with a peripheral neuropathy, 3 of whom had been found to have sensory impairment in bedside testing (fig. 2, middle panels). Vibration thresholds in the hand were elevated in only 1 patient. In the foot, however, vibration thresholds were abnormally high in 13 out of 20 patients (65%), including all patients with an electrophysiologically demonstrable polyneuropathy (fig. 2, lower panels). Vibration thresholds were also obtained from the ankle with similar results; 53% of patients had elevated thresholds at this site. Ten out of 17 patients without neuropathy had impaired vibratory perception in the foot and/or at the ankle. There was no correlation between tactile or vibratory thresholds and duration of disease, age of onset, severity of disease or thermal thresholds. All patients had at least one abnormal sensory threshold. Since only 7 had clinical sensory impairment, it follows that an unsuspected sensory deficit was found in 70% of patients. Three or more raised thresholds were found in 13 patients, of whom 12
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FIG. 2. Warm-cold limen (WCL), tactile threshold (TT) and vibration threshold (VT) plotted against age (in yrs) in patients with hereditary spastic paraplegia. Left panels correspond to the hand, right panels to the foot. Filled circles represent patients with a peripheral neuropathy. The least squares regression line (broken) and upper 95% confidence limit (solid line) for 124 normal controls are also shown. Note log scale for the ordinate in the lower four panels.
had involvement of sensory submodalities mediated by both large fibres (touch, vibration) and small fibres (warm, cold). With a simplified protocol relying on the thermal and vibratory thresholds at a single site in the foot, 19 patients would have been found to have impaired sensibility. Somatosensory evoked potentials Somatosensory evoked potentials (SEPs) to median nerve stimulation could be obtained in 17 out of 19 patients. Both patients with absent SEPs also had reduced peripheral
716
W. SCHADY AND A. SHEARD
sensory action potentials. Three patients had a delayed N9 peak recorded over the brachial plexus, one had a prolonged N9-N13 interpeak latency difference and 2 had prolonged N13 —N20 interpeak latencies. In all these cases the delay was modest, amounting to less than 2 ms outside the normal range. After excluding patients with a neuropathy, the amplitude of subcortical SEPs, both at the brachial plexus and over the cervical cord, did not differ significantly from that of normal controls. However, the amplitude of cortical SEPs was significantly reduced. In 14 patients with normal peripheral sensory conduction, the mean N20 potential amplitude was 2.8 ±1.1 /iV, compared with 3.8±2.0 fiV in control subjects (P < 0.02). Somatosensory evoked responses to tibial nerve stimulation were recorded in 10 patients without evidence of peripheral neuropathy. In 1 case they were absent bilaterally, while in 4 cases they were absent unilaterally but could be obtained from the other side. The mean amplitude of the P40 potential, when recordable, was 2.4 ±0.8 fiV in patients and 5.3 ±2.1 pV in control subjects (P < 0.001). The latency of the P40 peak was normal in all cases. Fourteen patients (60%) had an abnormality of either nerve conduction studies, somatosensory evoked potentials or both. DISCUSSION
Hereditary spastic paraplegia (HSP) presents a relatively uniform clinical picture in the majority of patients. In the uncomplicated form there is insidiously progressive lower limb spasticity, with moderate weakness and no lower motor neuron features. The disease may be transmitted as an autosomal dominant or, less commonly, as an autosomal recessive trait. This distinction is not always easy, as dominant disorders may show variable clinical expression. A family in point is our kinship 4, where all of 6 siblings had the disease, and neither parent was known to have been affected. Either autosomal dominant or autosomal recessive inheritance is possible. Inheritance may have been recessive in 2 other families (kinships 2 and 12), but there was no consanguinity and the parents were not examined, so autosomal dominant transmission again cannot be excluded. Since only patients with a clear family history were admitted to the study, there may be an over-representation of dominantly inherited kinships in our material. Subdivision of patients is possible on the basis of age of onset of symptoms. In a study of 22 families, Harding (1981) divided dominant HSP into two forms, namely type I, with an age of onset below 35 yrs, and type II, with onset usually over 35 yrs. In our families, 20 yrs was a better cut-off point between juvenile and adult-onset forms of HSP. By this criterion, 8 families were uniformly of juvenile onset and 6 families were of adult onset. On average, within the limitations imposed by our rather crude disability scoring system, the latter progressed twice as rapidly as the former. Harding (1981) also found that late onset is associated with a worse prognosis. Families have been reported in which HSP is associated with optic atrophy, extrapyramidal disease, deafness, amyotrophy or cerebellar ataxia (for review, see Harding, 1984). Twenty of our 23 patients had the so-called 'pure' form of the disease. One patient had upper limb amyotrophy as well as a paraparesis, a previously recognized
HEREDITARY SPASTIC PARAPLEGIA
717
association (Silver, 1966). Another patient had perceptive deafness and a third had optic atrophy. In the presence of an otherwise typical clinical picture and a positive family history, their inclusion in the series was thought justified. Six patients had reduced or absent peripheral sensory action potentials, implying that they had a polyneuropathy as well as corticospinal tract disease. None of them was similar to previously described cases of hereditary spastic paraparesis with sensory neuropathy, who suffered from a progressive ulcerating sensory polyneuropathy which overshadowed the pyramidal syndrome (van Epps and Kerr, 1940; Khalifeh and Zellweger, 1963; Koenig and Spiro, 1970; Cavanagh et al., 1979). The clinical picture in our patients was also quite unlike that of families with peroneal muscular atrophy with pyramidal features (Harding and Thomas, 1984), in whom the neuropathy predominates. Adrenoleukomyeloneuropathy was considered in kinship 4 but was thought to be unlikely by the demonstration of normal adrenal function tests in a male member of the family. Other authors have reported impaired sensation in some patients with otherwise uncomplicated HSP. Bickerstaff (1950) found defective lower limb sensitivity to vibration in 7 out of 43 examined members of a large kinship with HSP. In no case was any superficial sensory loss discovered. In 52% of the cases reported by Behan and Maia (1974), 27% of those of Harding (1981) and 60% of those of Boustany et al. (1987) there was a sensory deficit in the lower limbs. It was restricted to vibration sense and, in a few patients, joint position sense. Seven of our patients had sensory impairment on bedside testing, predominantly involving dorsal column submodalities, as in previous reports, though 4 patients had reduced pin prick perception, which in 1 case extended to the upper limbs. Four of these 7 patients were among the group in whom nerve impairment studies showed a peripheral neuropathy. Quantitative sensory testing (QST) was more revealing than bedside examination of sensibility. Our results show that some sensory abnormality is almost universal in the lower extremities of patients with HSP if sensitive enough methods are applied to detect it. QST is often considered excessively cumbersome for routine use, but our battery of tests at several sites in the hand and foot usually took no more than 45 min to apply. It allowed us to test a range of sensory submodalities, an evident advantage in view of the variability inherent in any form of sensory testing and the lack of correlation between the various thresholds. With a simplified protocol, relying on results obtained at a single site in hand and foot, QST need be no more time-consuming than standard electrophysiological tests, and yet our findings suggest that in some instances it may be more sensitive. While only 60% of our patients had abnormal nerve conduction studies and/or somatosensory evoked potentials, all had one or more abnormal sensory thresholds. The methodology of QST requires further discussion. For the sake of simplicity we chose the method of limits for measurement of cutaneous thresholds. Forced-choice techniques are psychophysically superior, since they reduce response bias and eliminate variability in reaction times (Dyck et al., 1984; Jamal et al., 1985), but they also lengthen the procedure. This is particularly important when several sensory submodalities need to be tested, as distractability will increase with fatigue. For thermal thresholds, the intrasubject variability inherent in the 'Marstock' technique presents a serious problem
718
W. SCHADY AND A. SHEARD
in longitudinal studies (Fagius and Wahren, 1981), but it should not invalidate the results of case control studies such as ours. The Marstock method has the added advantage of allowing measurement of pain thresholds (Fruhstorfer et al., 1976). With regard to vibration sense, the vibrameter that we employed has a pressure monitor which ensures that the probe is applied with a constant force, contrary to the standard biothesiometer which does not make allowances for variable damping of the vibratory stimulus (Goldberg and Lindblom, 1979). Lastly, we chose von Frey hairs to assess tactile sensitivity because, although they do not provide a fully controlled physical stimulus, they are cheap and produce a similar range of thresholds in fingers and toes to those obtained with more sophisticated techniques (Dyck et al., 1984). It should be emphasized that the methods used, and the testing sequence, were the same in patients and controls. The disturbance of cutaneous sensitivity detectable by QST affected all modalities. Most surprising was the increase in thermal thresholds in patients as compared with controls, especially in the lower limbs, where raised values were found in three-quarters of the patients. Heat pain thresholds in the foot were also increased, although less strikingly. This disturbance of 'spinothalamic' function applied regardless of whether patients with an electrophysiologically proven sensory polyneuropathy were excluded. There was no correlation between sensory thresholds and disease severity, disease duration or age of the patient. Our results, therefore, do not support the view expressed by some authors that sensory loss in HSP is increasingly common with advancing age (Schwarz and Liu, 1956; Behan and Maia, 1974). All previous reports of clinical sensory impairment in uncomplicated HSP refer to modalities mediated by large fibres. Our finding of abnormal vibratory and tactile thresholds was therefore less unexpected than the results of thermal testing. Although patients with a polyneuropathy had the highest thresholds, vibration perception was impaired in the foot or at the ankle in over half of those without a neuropathy. This suggests central nervous system dysfunction, a conclusion further supported by the SEP results. After excluding patients with abnormal peripheral conduction, the amplitude of cortical SEPs from the lower limbs was less than half that of healthy controls. Cortical SEPs from the upper limbs were also significantly reduced, though to a lesser extent. Abnormalities in somatosensory evoked potentials in HSP have previously been reported by other authors (Pedersen and Trojaborg, 1981; Thomas et al., 1981; Dimitrijevic et al., 1982). Neuropathological studies have shown dorsal column degeneration in some patients with HSP (Schwarz and Liu, 1956; Behan and Maia, 1974), in keeping with the neurophysiological evidence of posterior column dysfunction. By contrast, there are no reports of spinothalamic tract degeneration in HSP. Nonetheless, our data indicate that afferent pathways mediating pain and thermal sensibility are not spared. There are pointers to both peripheral and central nervous system disease. Six of our patients clearly had a neuropathy. The others might be argued to have had a small fibre neuropathy, since nerve conduction studies assess function in large myelinated fibres only. On the other hand, some of the highest thermal thresholds correspond to patients with normal peripheral conduction, suggesting spinothalamic tract involvement in some cases.
HEREDITARY SPASTIC PARAPLEGIA
719
Whatever the precise site of damage, the disease may extend to the upper limbs in a few patients, as evidenced by abnormal sensory thresholds or exaggerated tendon reflexes. It is interesting that 5 out of the 6 patients with a neuropathy were members of the same family. This may explain why the proportion of patients with neuropathy in our series is greater than that of previous authors. A number of reports of HSP with normal peripheral nerve function concern single families (Holmes and Shaywitz, 1977; Dimitrijevic et al., 1982) or only 3 families in the study by McLeod et al. (1977). If neuropathy does not occur randomly in HSP but within genetically distinct subgroups, it is unlikely to be recognized unless large numbers of families are studied. We wish to emphasize, however, that even in the absence of a polyneuropathy sensory impairment is common in HSP, pointing to the kind of multisystem involvement that is associated with most familial nervous system degenerations. ACKNOWLEDGEMENTS We wish to thank Drs R. G. Lascelles, D. Neary, M. Sambrook and D. I. Shepherd for referring patients. Our thanks also to Professor U. Lindblom and Dr A. E. Harding for reviewing the manuscript, to Ms L. Hunt for assistance with statistical analysis, and to Dr D. Donnai for advice on genetic aspects. REFERENCES BEHAN WMH, MAIA M (1974) StrumpeH's familial spastic paraplegia: genetics and neuropathology. Journal of Neurology, Neurosurgery and Psychiatry, 37, 8 — 20. BICKERSTAFF ER (1950) Hereditary spastic paraplegia. Journal of Neurology, Neurosurgery and Psychiatry, 13, 134-145. BOUSTANY R-MN, FLEISCHNICK E, ALPER CA, MARAZITA ML, SPENCE MA, MARTIN JB, KOLODNY EH
(1987) The autosomal dominant form of 'pure' familial spastic paraplegia: clinical findings and linkage analysis of a large pedigree. Neurology, Cleveland, 37, 910—915. CAVANAGH NPC, EAMES RA, GALVIN RJ, BRETT EM, KELLY RE (1979) Hereditary sensory neuropathy
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