Head tremor was more often intermittent (11,3%) than not (5.7%). The intermittent tremors were invariably of the 'no-no' variety and could often be induced when the patient talked or concentrated on writing. The more persistent head tremors were present when sitting or standing, but not where the head was completely supported (rest), and were of a complex type with both 'yes-yes' and 'no-no' component (either could be predominant). Tremor of the jaw, voice, tongue and face were never seen in isolation and were only evident in patients with quite severe upper limb tremors. The likelihood of tremor affecting the cranial musculature increased with the severity of upper limb tremor. Tremor of osbicularis oculi was most obvious whilst the eyes were closed. Tremulousness of orbicularis oris, mentalis and masseter were most visible during normal conversation. None of the secondary cases had evidence of parkinsonian dystonia or other neurological disease. Cogwheeling could be palpated in four cases (7.6%) but would disappear when the subjects relaxed fully and Froment's' sign was noted in one other patient (1.9%). Rigidity was never apparent and arm-swing invariably normal. Wartenberg's test was negative in every case. Children. Amongst 14 children aged under 15 years there were six possible cases (age range 2-13 years). Four of the remaining two had symptoms produced by tremor Natural history It was typical for individuals to state that they had felt shakes 'inside' for several months prior to developing overt essential tremor. Later this would progres to cause an intermittant action tremor which appeared when the affected person was excited or fatigued, a situation that in many instances led to that person being labelled 'nervous'. Subsequently, the tremor would become more persistent but could be voluntarily suppressed for short periods of time, so that little disability occured. At this stage the postural tremor often appeared to be jerky, with tremor arriving in flurries that lasted for no more than a few seconds. In the younger, mild cases, tremor was most evident for an instant when a new posture was adopted. It could also be seen at an early stage to interrupt slow voluntary pronation-supination movements of the wrist. Subsequently, as tremor increased in amplitude it became more autonomous and oscillatory. It was then more difficult to control and caused disability. However, even with the most severe upper limb tremors, considerable fluctuations in amplitude were evident and at times tremor would virtually cease, even when a posture was maintained, only to return a few seconds later. Tremor amplitude was also significantly altered by changes in posture, task and the general state of activity of the individual, but could still be voluntarily suppressed, to some extent, for short periods of time. Tremor frequency was also observed to vary with different tasks and positions of the arms, as has been reported elsewhere (Bain et al., 1993b). Hunger, emotion, fatigue and temperature (e.g. hot baths) exacerbated tremulousness. Tremor severity in index and secondary cases The means and ranges for the severity of head, upper and lower limb postural tremors are shown in Table 2, from which it can be seen that the brunt of hereditary essential tremor falls on the upper limbs. The severity of upper limb tremor (as assessed by spirography and the clinical rating scale scores) worsened with age and the duration of tremor (Table 3). However, there was no relationship between tremor severity measured in these ways and the age at which tremor was first noticed (age of onset) (Table 3). The severity of leg tremor amongst the index and secondary cases was highly correlated with that in the upper limbs (corrrelation coefficient = 0.43, P <0.001). Severity of upper limb postural tremor and tremor evident in spirals did not significantly differ between male and female cases or amongst those cases with a maternal rather than a paternal mode of inheritance (Wilcoxon's rank sum test). Disability and handicap in index and secondary cases All the index patients and 81% of the definite secondary cases completed and returned the disability and handicap questionaires. All of the index patients and the majority (79%) of those secondary cases who returned their questionaires documented some disability (64% of all definite secondary cases). The relationships between the extent of disability and the ages of the affected cases, the age at onset and duration of tremor are shown in Table 3. Decade specific disability is shown for all cases (inclusive and exclusive of possible cases) in Fig. 4A. Hereditary essential tremor never produced ----------------------------------------------------------- Table 2 The severity of tremor in Archimedies spirals rated from 0 (none) to 10 (most severe) and the postural tremors of the upper limbs, lower limbs and head which were also scored from 0 (none) to 10 (most severe) using a clinical rating scale Index Affected relatives patients Excluding Including possible possible cases cases (i)Spiral score (0-10) Mean 3.8 2.6 2.3 Range 0-6.5 0-5 0-5 (ii)Right arm (0-l0) Mean 1.7 1.1 1.0 Range <4.0 0.2-4.0 0.1-4.0 (iii)Left arm (0-10) Mean 1.5 1.0 0.9 Range 0.3-4.0 0.2-4.0 0.1-4 (iv)Right leg (0-10) Mean 0.3 0.2 0.2 Range <1.7 <1.0 <1.0 (v)Left leg (0-10) Mean 0.3 0.2 0.2 Range <1.7 <1.3 <1.3 (vi)Head (0-10) Mean Negligible Negligible Negligible Range <0.5 <1.0 <1.0 ---------------------------------------------------------- Table 3 Correlation coefficients (r-values) for the relationships between (i) tremor severity in the right anm (graded clinically from 0 to 10); (ii) tremor in spirals (graded from 0 to 10); (iii) disability (%) and the patients' ages, ages at tremor onset and tremor deviations Index and definite Spiral score Right arm tremor Disability secondary cases severity Age 0.49* 0.60* 0.36* Age or tremor onset 0.05 0.23 0.07 Duration of tremor 0.49* 0.3l** 0.28*** __________________________________________________________ Significant at: *P < 0.001; **P < 0.01; ***P < 0.05. The significance levels were not altered by the inclusion of possible cases. --------------------------------------------------------- disability before the age of 15 years. The frequency with which difficulties were documented with each item on the disability questionnaire is shown in Appendix I. The most commonly affected tasks were those normally performed with the dominant hand (Appendix 1). Perhaps surprisingly several patients reported that bathing was difficult, explaining that they would become more tremulous in a hot environment. and 30% of index patients and 9% of secondary cases had some difficulty with stairs. There was no significant difference in the degree of disability found in men compared with women or among those cases who had paternal rather than maternal inheritance (Wilcoxon's rank sum test). The extent of social handicap and the various situations in which this was experienced are shown in Table 4, Sixtie (80%) of the index cases and 47% of those secondary cases who returned their questionnaires (38% of all definite secondary cases) reported that they were handicapped some way by their tremor; generally this was because of both physical impairment and embarrassment rather than either factor alone. Five (25%) of the index patients and 12% of the definite secondary cases had been forced to change jobs or take early retirement because of tremor. Furthermore 12 (60%) of the index patients and 19% of the definite secondary cases had not applied for a job or promotion because of tremulousness. The majority (65%) of the index patients and 33% of the definite secondary cases no longer dined out. Decade-specific handicap is shown for all cases (including and excluding possibles) in Fig. 4B. Fifty percent of cases were handicapped by the fifth decade and 80% by the sixth. The subsequent decline is probably caused by the social consequences of retirement. Clinical associations The conditions affecting two or more index and definite secondary cases are reported in Table 5A and the number of families in which co-segregation was observed between hereditary essential tremor and either classical migraine (migraine associated with transient focal neurological symptoms) or the restless legs syndrome or hypertension are shown in Table 5B. Alcohol responsiveness and effect of treatment Eleven of the index patients (55%) and 25 (47.2%) of these (definite) secondary cases reported that drinking between ----------------------------------------------------------- Table 4 The impact of hereditary essential tremor upon livelihood and social behaviour (handicap) Index Reason for handicap Secondary Reason for handicap cases cases* E P E+P E P E+P -- -- - --- -- - --- (a) Percentage forced to change job/retire 25 - - - 12 - - 12 (b) Percentage not to apply for a job/promotion 60 20 5 35 19 5 5 9 (c) Percentage no longer shopping alone 55 15 5 35 7 0 2 5 (d) Percentage no longer eating out 65 10 0 55 33 16 5 12 (e) Percentage no longer attending parties 50 0 0 50 23 12 2 9 (f) Percentage no longer able to practise their favourite sport/hobby 30 5 15 10 19 7 7 5 (g) Percentage no longer travelling by public transport 35 10 15 10 7 0 0 7 (h) Percentage no longer driving a car 20 0 10 10 7 0 2 5 (i) Percentage no longer going on holiday 35 10 5 20 7 5 0 2 *Of those definite secondary canes who returned completed questionnaires (81.1% of all definite secondary cases). Handicap caused by: P = physical impairment; E = embarrassment; P+E = both physical impairment and embarrassment. ---------------------------------------------------------- ----------------------------------------------------------- Table 5 Possible clinical associations with hereditary essential tremor (A) Conditions affecting two or more index or definite secondary cases No. Percentage affected affected classic migraine 19 26.0 Left handedness 9 12.3 Hypertension 8 11.0 Non-insulin dependent diabetes mellites 4 5.5 Restless legs syndrome 3 4.1 Osteoarthritis 3 4.1 Cataracts 2 2.7 Duodenal ulcers 2 2.7 (B) Conditions co-segregating with essential tremor within one or more kindreds No. of families Co-segregation ratio co-segregating Affected* Unaffected^ Classical migraine 3 0.67(10/15) 0.0 (0/8) Restless leg syndrome 1 1.0 (2/2) 0.0 (0/6) Hypertension 1 1.0 (3/3) 0.0 (0/0) *The ratio of the number of cases with either migraine, restless leg syndrome or hypertension who also have tremor divided by (be total number of kin definitely affected by tremor (affected); ^ the ratio of thc number of cases who have one of these three conditions but do not have tremor divided by the total number of atremulous kin (unaffected). ----------------------------------------------------------- and four units of alcohol would virtually abolish their tremor for -2-4h but the tremor would rebound and be worse the following day. In spite and because of the transient nature response two index patients (10%) and two secondary cases (4%) admitted to being dependent upon alcohol and would not go out of the house without a drink. Four other index cases and 10 secondary cases did not benefit from alcohol and five further index cases and 18 secondary cases did not drink. The degree of homogeneity or heterogeneity of the responses to alcohol within the kindreds was variable. (i) amongst the families of the 11 index patients who were alcohol responsive, all affected relatives were alcohol responsive in nine of the kindreds; in one kindred the effect of alcohol on the other affected members of the family was not known; and in one family responders and non-responders coexisted; (ii) amongst the families of the four unresponsive index patients, two kindreds were homogeneously unresponsive and two families exhibited heterogeneity; (iii) amongst the families of the five index patients in whom the response to alcohol was not known, three were homogeneously responsive, one unresponsive and one included both responders and non-responders. Thus, in summary, 15 of the families showed homogeneity and four heterogeneity of responsiveness to alcohol (for the remaining family the facts are not known). Twelve index patients had been prescribed propranolol of whom seven (58%) had experienced some benefit. which varied from modest to substantial. Three other patients (15%) were taking primidone with good results. Only four affected relatives (8%) had received any treatment for their tremor-two responding to propranolol and two to primidone. Adverse effects of drugs Three cases with long-standing postural tremor had been prescribed prochlorperazine for unrelated symptoms. In each case tremor severity was greatly exacerbated and this effect was evident within days of taking the drug. Two of these cases also developed a marked upper limb rest component to their tremor; this disappeared when prochlorperazine was withdrawn but in both cases a degree of cogwheeling was evident 1 year after the drug had been stopped. Biological fitness The mean number of children born to the index patients was 2.10 (SD +/-2.17) and was 2.63 (SD +/-2.12) if only index patients over 35 years old were included. These figures are similar to general population data in the United Kingdom (Office of Population Censuses and Surveys 1984,1987). Segregation analysis The proportions of affected to unaffected siblings of index patients and offspring of index patients and their affected relatives are shown in Table 6. The null hypothesis that the actual proportions of affected to unaffected relatives would not differ from the expected ratio of 1:1 was tested using the formula given by Roberts and Fensbrey (1978) which includes Yates' correction. The actual proportions did not significantly differ from 1:1, irrespective of whether possible cases were considered to be affected (X2 = 0.387, P > 0.05) or unaffected (X2 = 0.688, P > 0.05). A plot of the ages at tremor onset for the index patients versus that of their (definitely) affected relatives showed that both young and late onset index cases had relatives with both young and late onset tremors (Fig. 5). There was a slight trend for individuals within the same family to have a similar age of onset but this did not reach statistical significance {Spearman correlation coefficients: 0.22 (excluding) and 0.17 (including possible cases), P > 0.05]. Genetic counselling The risks of a currently unaffected child of a parent with hereditary essential tremor developing essential tremor disability or handicap are shown in Table 7. The risk of developing hereditary essential tremor after the ages of 10 and 50 years are <20 and <6%, respectively. Discussion The purpose of this study was to delineate the clinical features of hereditary essential tremor. We approached this by selecting 20 index patients with incontrovertible hereditary essential tremor and then examining their relatives so as to define the phenotype of the gene or genes involved. Relationship to other neurological diseases We did not find any dystonia amongst our subjects. Several previous studies have included patients with abnormal dystonic postures under an expansive definition of 'essential tremor' (Critchley, 1949, 1972; Hornabrook and Nagurney, 1976) ----------------------------------------------------------- Table 7 Data for giving generic counselling to an apparently unaffected child who has a parent with hereditary essential tremor Age Risk of Approximate percentage risk of developing a of developing tremor (T),disability(D)or handicap (H) child tremor (%) by the ages of (years) 20 years 30 years 40 years 60 years T D H T D H T D H T D H 0 46 30 18 9 33 19 13 40 34 17 45 44 38 5 41-42 24 14 7 27 16 11 35 30 15 40 40 34 10 38-39 20 12 6 24 14 11 32 28 13 37 37 32 15 28-29 8 5 2 12 7 5 21 19 9 27 27 23 20 22-23 4 3 2 14 10 6 20 20 18 25 19-20 11 12 5 17 17 15 30 18-19 11 12 5 17 17 15 35 15-17 7 8 3 13 13 11 40 9-1l 7 7 6 45 7-9 6 6 5 50 5-6 3 3 3 55 3-5 0 0 0 60 0 For example, at birth (0 years), (the risk of ever developing hereditary essential tremor is 46%; the risks of that individual having tremor, being disabled by it, or handicapped by it, by the age of 20 years are 30,18 and 9%, respectively. ----------------------------------------------------------- Rajput et al., 1984; Martinelli et al., 1987; Lou and Jakovic, 1991). In one of these studies, Lou and Jankovic (1991) reported that amongst 350 patients diagnosed as having 'essential tremor', 47% had dystonic posturing, which was equally distributed amongst their familial and sporadic cases. However, in the light of our findings and the observations that patients with idiopathic and hereditary torsion dystonia often exhibit tremor (Zeman et al., 1959; Marsden and Harrison, 1974; Couch, 1976; Baxter and Lal, 1979; Sheehy and Marsden, 1982; Fletcher et al., 1990, 1991) it would appear that these accounts of 'essential tremor', in fact, describe at least two separate diseases. Similarly, the absence of nystagmus or other cerebellar signs in our subjects suggests that papers including patients with these features (Nettleship, 1911; van Bogaert and de Savitsch. 1937; Critchley, 1949, 1972) were not describing a single entity. Furthermore, there were no cases of Parkinson's disease or signs of peripheral neuropathy amongst our kindreds. Evidently, much of the previous literature on 'essential tremor' was describing several diseases in which postural tremor occurred and resembled that seen in hereditary essential tremor. The clinical characteristics of hereditary essential tremor The median age of onset was 15 years for our index patients and between 14.5 and 15 years for the secondary cases (Table 1). which is in accordance with the descriptive findings of Critchley (1949) and Jager and King (1955). However, the actual age of onset is likely to precede the reported date which would tend to shift the true cumulative age of onset plot to the left (Fig. 2). The distributions of ages at tremor onset of the index patients and secondary cases were bimodal (Figs I and 3, respectively), as has been found in a previous study (Gerstenbrand et al., 1982), which might suggest that two abnormal genes might be involved. However, the 'late onset' (over 35 years) index cases had affected relatives with early onset tremors and there was no tendency for late onset cases to cluster within particular families (Fig. 5). These results do not support a two (distinct) gene hypothesis (Harris and Smith, 1947) but indicate an individual temporal variability to expressing the phenotype. Examination of the pedigrees and segregation ratios indicated an autosomal dominant disorder and there were no detectable instances of reduced penetrance. Penetrance was complete by the age of 65 years. These findings are in agreement with the observations of Jager and King (1955), who documented a single large pedigree in Utah through Larsson and Sjogren (1960) in their epidemiological study of northern Sweden, except that the latter found a mean age at tremor onset of ~50 years perhaps because the information on ~50% of their 210 'cases' was obtained after the patients had died. Our data (Figs 2 and 4) can be operated on with Bayesian statistics and be used for genetic counseling (Table 7). Thus, the risk of a clinically normal 20-year-old offspring of an affected individual developing tremor is ~23%. The likelihood of this offspring developing a disability or handicap due to hereditary essential tremor before the age of 60 years (during working life) are ~20 and 18%, respectively. The proportions of affected men and women were not significantly different for our cases, which is in accordance with Jager and King's (1955) description and the epidemiological surveys conducted by Hornabrook and Nagumey (1976), Rajput et al. (1984) and Bharucha et al. (1988) on 'essential tremor' in their respective communities. The biological fitness of the index patients who were over the age of 35 years and thus considered to have completed their families was not diminished. Biary and Koller (1985) suggested that the incidence of left handedness in patients with essential tremor (17%) was greater than in a normal control population (8%). Our figures of 15% for index and 11.3% for definite secondary cases provide some support for this notion. Tremor invariably commenced in one or both of the upper limbs of our subjects. No examples of isolated head, tongue. voice, jaw, trunk and leg tremors were seen either in our (selected) index patients or the secondary cases. These entities have all been described in the literature as manifestations of essential tremor (see Introduction), so either these 'isolated' tremors represent rare forms of 'essential tremor' or more likely result from other disease processes. Dystonia can produce tremor alone (Fletcher et al., 1990). The most common type of focal dystonia is spasmodic torticollis (Marsden and Fahn, 1982) and isolated head (and trunk) tremor may occur as a manifestation of that condition (Rivest and Marsden, 1990). Tremors of the jaw, face, tongue and voice can occur in oromandibular dystonia, lingual dystonia and spasmodic dysphonia and at least some cases of isolated tremor at these sites may be produced by dystonia. Isolated leg tremor suggests the diagnosis of Parkinson's disease, particularly if a rest component is present, or primary orthostatic tremor if it occurs on standing with a frequency of between 14 and 16 Hz (although transient epochs of period doubling have been recorded in this condition (Thompson et al., 1986; Rothwell, 1989; Britton et al., l992a). Indeed, most patients with isolated leg tremor of frequencies between 4 and 6 Hz have a reduced [18F]dopa uptake into the putamen as seen on PET studies, a finding characteristic of Parkinson's disease (Brooks et al., 1992). It is also conceivable that isolated leg tremor occurs in dystonia, but our findings suggest that hereditary essential tremor is nor a likely culprit. The onset of tremor was reported to be in 'both hands' by 80% of the index and 83% of the secondary cases. In the remainder, with one exception. tremor commenced in the dominant hand. However, in all but one mild case both hands became affected and there were no examples of prominent unilateral tremor. A severe persistant postural tremor of one arm is more likely to be the result of dystonia, parkinsonism or a structural lesion, than hereditary essential tremor. A 'hemiparetic' pattern of tremulousness was never evident in this study. In 10% of our index patients and 66% of the definite secondary cases the upper limbs were the only sites affected, but initial spread from the arms to the legs (35% of index and 26.4% of secondary cases) was more commonly reported than spread directly from the arms to the head (30% of index and 7.6% of secondary cases). This is contrary to the opinions expressed in several previous accounts (Critchley, 1949. 1972; Larsson and Sjogren, 1960; Marshall, 1962; Lou and Jankovic, 1991) but most of these studies included patients with torticollis. In descending order of frequency, tremor of the legs, head, voice, tongue, face and jaw were seen and these occurred more often in individuals with severe postural tremor of the arms. No true isolated truncal tremors were observed, those encountered being invariably due to transmission of leg tremor. No rest tremors were detected whilst the subjects were completely relaxed and in those cases where 'cogwheeling' was palpable, it would disappear when the subjects' voluntary muscle activation declined. Rigidity at the wrists and elbows or reduced shoulder swing (Wartenberg's sign) were not encountered and no 'pill-rolling' tremors were seen. We suspect that previous reports of rigidity (Larsson and Sjogren, 1960; Salisachs, 1978; Salisachs and Findley, 1984) and 'pill-rolling' (Larsson and Sjogren, 1960; Hornabrook and Nagurney. 1976) in patients with 'essential tremor' may have been due to coincidental pathology or exposure to anti-dopaminergic drugs. Indeed, [18F]dopa studies have demonstrated reduced uptake of tracer into the putamen to a degree found in Parkinson's disease in a proportion of patients (two out of 12) with sporadic postural arm tremor (Brook et al., 1992). In contrast, putamenal [18F]dopa was within the normal range in eight cases of hereditary essential tremor furthermore, in a study of twins with Parkinson's disease two co-twins with postural arm tremor but without rigidity or bradykinesia had reduced [18F]dopa uptake into the putamen (Burn et al., 1992). Accordingly, some patients with postural arm tremor but no family history of essential tremor may well have Parkinson's disease (or dystonia) rather that essential tremor. Kinetic tremor of the upper limbs was almost ubiquitous but the mid-movement component only achieved an amplitude comparable with the postural component (fingers held close to the nose with the elbows elevated) in ~25% of index and 12% of secondary cases. A true 'intention' component, in which tremor amplitude was greater in the terminal phase of the nose to finger test compared with maintained posture, occurred in ~15 and ~6% of the index and secondary cases, respectively. The tremor component most evident in our cases was that released at the end of movement for the first few moments of a maintained posture until the hands were steadied. Tremor then became more apparent as the new position was held. No dysmetria was seen and in this respect the terminal component of hereditary essential tremor differs from that encountered in diseases of the cerebellum or its connections. Head tremor occurred in seven index patients (35%) and in nine secondary cases (17.6%) but was mild (Table 2) and always much less than that of the arms. In nine cases an intermittent 'no-no' type of tremor was evident. In the remainder, tremor was persistant; one had a 'yes-yes', three a 'no-no' and three 'complex' tremors, in which both 'yes-yes', 'no-no' and/or oblique movements were present. Consequently, mild or intermittent 'no-no' tremors account for 75% of the head tremors seen in this study, although other types, albeit of modest severity, did occur. Significantly, Jager and King (1955) reported only 'no-no' head tremors in their large kindred but other authors have described 'yes-yes' head tremors to be more frequent (Findley, 1984; Lou and Jankovic, 1991). Leg tremor was present in 45% of the index patients and ~30% of the secondary cases. It was invariably bilateral and highly symmetrical. The severity of postural tremor in the legs was much less than that in the arms (Table 2) and there was a significant correlation between the severity of postural upper and lower limb tremor when the latter was present. However, leg tremor was a serious problem in only two index (20%) and three secondary (5.7%) cases, although several others had difficulty with stairs. It differed from primary orthostatic tremor in two respects: first, our patients were equally troubled by their leg tremors irrespective of whether they were walking or standing; secondly, frequencies of their leg tremors varied from 7.5 to 10 Hz. Tremor severity, disability and handicap The patients' reported ages at tremor onset had no relationship to the severity of tremor, as assessed by rating postural upper tremors, grading spirals or patient self-reported disability (Table 3). Hubble et al., (1989) also concluded that the reported age at tremor onset was not related to outcome. The ages of our index patients and their affected relatives were highly correlated with the severity of upper limb postural tremor, the tremor present in spirals and the extent of disability (Table 3). Similarly, tremor duration was significantly correlated with both measures of tremor severity and disability (Table 3). Men and women were affected with equal severity and experienced equal disability. The sex of an affected parent had no influence on the tremor severity or disability suffered by an affected child. Our results also show a highly significant correlation between the severity of tremor in each arm and thus a high degree of symmetry. Larsson and Sjogren (1960) and Marshall (1962) were also of the opinion that 'essential tremor' was generally a symmetrical condition but others have disagreed (Critchley, 1949; Biary and Koller, 1985; Findley, 1987). Disability began in the second decade and subsequently increased both in terms of prevalance (Fig. 4A) and degree (Table 3) with age. There is a variable period of time from the onset of tremor when affected individuals can usually control or suppress their increasingly abnormal postural tremors, so that the degree of functional impairment is limited. However, this ability to compensate for tremor, or control it, during specific activities wanes as tremor severity worsens, so that a surprising number of functions become difficult to perform (Appendix 1). All the index patients and 79.1% of the secondary cases who responded to the questionnaire reported that they had experienced difficulties with one or more of the items listed in Appendix 1. However, only 34% of the definite secondary cases had consulted a doctor about their tremor and only 7.6% had received suitable treatment; most were sinsply told that they were 'old' or 'nervous'. Some degree of social handicap was reported by 85% of the index patients and 46,5% of those definite secondary cases who returned questionnaires. Handicap began in the later half of the second decade and increased with age reaching a peak in the sixth decade, when 86% of cases aged between 60 and 70 years reported that tremor was imposing some restriction on their social activities (Fig. 4B). Even tremors of modest amplitude caused embarrassment and curtailed social activities (Table 4). In view of this, it is interesting to note how few secondary cases sought treatment, even on an 'as required' basis. In part this may be because they perceived that the responses of the index cases (particularly tc propranalol) were always partial (Table 2) and associated with side-effects. This is illuminating as several clinical trials have shown that essential tremor at first responds impressively to propranolol, primidone or phenobarbitone when the efficacy of these drtigs was measured by accelerometry but long-term functional improvement is much less easily obtained (Baruzzi et al., 1983; Larsen and Calne, 1983; Findley and Cleeves, 1985; Koller, 1984; Koller et al., 1986) Significantly, in a recent study, no correlation was found between the results of accelerometry and the self-reported disability of 20 patients with postural tremor (Bain et al., 1993a). Two to four units of alcohol virtually abolished tremor for 2-4 h in ~50% of cases but it was invariably worse the following day. Fifteen (75%) of the families had homogeneous responses to alcohol; the tremors of either 100% of the affected members of each of these kindreds responded to alcohol or none responded at all. However, in four families 20%) definite heterogeneity of alcohol responsiveness was observed within each kindred. Classical migraine proved to be the condition most commonly associated with hereditary essential tremor occurring in 26% of all definite cases. It is of interest that in three of the families (15%) classical migraine and essential tremor were inherited together with a co-segregation ratio of 10:15 (0.67) (Table 5). John Cottingham "KNOWLEDGE is of two kinds: we know a subject, or we know where we can find information upon it." [log in to unmask] Dr. Samuel Johnson