A study of hereditary essential tremor
 
P.B. Bain,[1] L.J. Findley,[2] P D. Thompson,[1] M.A. Gresty,[1]
J.C. Rothwell,[1] A.E. Harding  and C.D. Marsden[1]
 
[1] MRC Human Movement and Balance Unit, Institute of Neurology,
London and [2] The Regional Centre for Neurology and
Neurosurgery, Oldchurch Hospital, Romford, UK
 
Correspondence to: Dr P.G. Bain. MRC Human Movement and
 
Balance Unit, Institute of Neurology, Queen Square. London WCIN
3BG, UK
 
Summary
 
Twenty index patients with hereditary essential tremor and their
kindreds were studied to define the phenotype of this condition.
Ninety-three first degree and 38 more distant relatives were
examined; 53 definite and 18 possible secondary cases were
identified. The age of tremor onset was bimodally distributed
with a median at ~15 years. Segregation analysis indicated
autosomal dominant inheritance and penetrance was virtually
complete by the age of 65 years. There were no examples of the
disease skipping a generation. Men and women were affected in
equal proportions. About 50% of cases were alcohol responsive.
In the majority of families alcohol responsiveness was either
consistently present or did not occur but in 20% of kindreds
definite heterogeneity of responsiveness was encountered within
each family. The typical phenotype was a mild symmetrical
postural tremor of the upper limbs. Tremor of the legs, head,
facial, voice, jaw and tongue occurred but never in isolation
and rest, task specific (e.g. primary writing tremor) and
orthostatic tremors were not found. Head tremor was invariably
mild and 75% was of a 'no-no' type. Dystonia (torticollis and
writers cramp) were not encountered, a finding which strongly
suggests that many previous studies of 'essential tremor' were
contaminated by cases of idiopathic or hereditary torsion
dystonia. No association with Parkinson's disease was found but
classical migraine occurred in ~26% of cases and co-segregated
with tremor. The severity of arm tremor (assessed using a
clinical rating scale and by scoring tremor in Archimedes
spirals) and disability increased with advancing age and
increasing tremor duration. but there was no correlation between
age at tremor onset and either tremor severity or disability.
Men and women were affected with equal severity. The sex of the
affected parent had no influence on the severity of tremor or
the degree of disability experienced by an affected child.
Disability commenced in the second decade and progressively
increased. All the index patients and 59% of the definite
secondary cases had tremor induced disabilities. Eighty five
percent of index patients and 38% of secondary cases also
reported some degree of social handicap. Twenty-five percent of
index patients and 12% of secondary cases had been compelled to
change jobs or retire. Biological fitness was normal.
 
Key Words: hereditary essential tremor; phenotype; segregation
analysis
 
Introduction
 
The concept of hereditary essential tremor evolved from the
observations that tremor could be familial (Most, 1836),
present in adolescence and persist throughout life (Sinkler,
1886). Many detailed reviews by Critchley (1949, 1972), Hassler
(1953), Jager and King (1955), Larsson and Sjogren
(1960), Marshall (1962), Murray (1981), Larsen and Calne (1983).
Findley (1986), Hubble (1989), Lou and Jankovic (1991) Koller et
al (1992) have established that the
impact of essential tremor falls predominantly on the upper
limbs and that it may produce tremulousness of the head, legs,
trunk, voice, jaw, and facial muscles. Typical
essential tremor manifests as a postural tremor (of the arms)
but kinetic. intention and resting components have been reported
(Critchley, 1949, 1972; Davis and Kunkle, 1951; Marshall, 1962;
Findley, 1987). At first tremor may appear intermittently during
periods of excitement (Critchley. 1949; Marshall. 1962) but it
usually progresses to become permanent, although the amplitude
can fluctuate.  and remissions have been described (Kreiss,
1912). Tremor is inevitably worsened by emotion as well as
hunger, fatigue and extremes of temperature (Critchley, 1949,
1972). Conversely, essential tremor is under some degree of
voluntary control and can be suppressed during the performance
of skilled manual tasks, at least for short periods of time
(Critchley, 1949; Jager and King, 1955; Bain et al., l993b).
 
 Several neurologists have considered a 'yes-yes' type of head
tremor (tremblement affirmatif) to be characteristic of the
condition (Findley, 1984; Lou and Jankovic, 1991), whilst others
report that a 'no-no' tremor (tremblement negatif) was more
common (Jager and King, 1955; Critchley, 1972) and complex
(oblique) head tremors have also been described (Critchtey,
1949; Biary and Koller, 1985). There is further disagreement
concerning the usual mode of onset and pattern of spread. Some
authors have described an asymmetric onset in one or other hand,
as the norm (Critchley, 1949) and Findley (1987) considered that
the retention of this asymmetric pattern was inevitable; whilst
other accounts have indicated that a symmetrical onset and
picture were more usual (Larsson and Sjogren, 1960; Marshall,
1962). Most authoritative accounts have agreed that, once the
upper limbs were affected, 'upward' spread to the head, face,
tongue or jaw was more common than involvement of the legs
(Critchley, 1949, 1972; Larsson and Sjogren, 1960; Marshall,
1962; Lou and Jankovic, 1991). However, hemitremulous states in
which tremor appears in an arm and the ipsitateral leg have been
documented, albeit rarely (Critchley. 1949; Larsson and Sjogren,
1960).
 
Inheritance
 
 Hereditary essential tremor is believed to be caused by an
autosomal dominant mutation (Critchley, 1949; Davis and Kunkle.
1951; Larsson and Sjogren. 1960) but the extent of penetrance is
contentious. Larsson and Sjogren (1960) and Rautakorpi (1978)
concluded from their own studies that complete penetrance had
occurred 'by the age of 70 years or shortly thereafter' but
others suggested that penetrance is incomplete (Marshall, 1962;
Critchley, 1972; Findley, 1984).
 
 Sporadic cases of essential tremor have also been widely
reported (Critchley, 1949, 1972; Marshall. 1962; Hubble et al.,
1989; Lou and Jankovic. 1991; Koller et al., 1992) and have
always been considered to be the same entity as the hereditary
form of the disease, an assumption that has never been formally
questioned. The proportion of patients with essential tremor
reporting that at least one other relative was affected has
varied in different studies from 17 to 70% (Marshall. 1962;
Hornabrook and Nagurney, 1976; Rautokorpi, 1978; Aiyesiloju et
al., 1984; Rajput et al., 1984). In part these diverse figures
are the result of relying upon patients' histories rather than
an examination of their relatives.
 
Age of onset
 
 Although essential tremor can occur at any age (Critchley 1949;
Findley, 1984) the peak age or onset has not been well
established. Critchley (1949) considered 'adolescence or early
adult life' to be the most usual age of onset. Gerstenbrand et
al. (1982) and Lou and Jankovic (1991) found a bimodal
distribution with peaks in the second and fifth decades, while
Larsson end Sjogren (1960) concluded that the disease seldom
begins in youth or at an advanced age but often commenced at
about the age of 50', an observation which in broad agreement
with the mean ages of onset (37 years) obtained from the data of
other studies (Critchley 1972; Koller et al., 1992). Critchley
(1949). having studied the family trees in several early papers,
pointed out that the phenomenon of 'anticipation', the tendency
for tremor to present at an earlier age in successive
generations was evident in these kindreds. No one else has found
evidence for this observation (Hubble et al., 1989) and,
although Larsen and Calne (1983) thought it might have been an
artefact, this has recently become a controversial issue.
 
Epidemiology
 
 Essential tremor has been established as a multi-racial
disorder following the epidemiological surveys carried in
Scandinavia (Larsson and Sjogren. 1960; Rautakorpi et al.,
1982), the USA (Haerer et al., 1982; Rajput et al., 1984 Africa
(Longe, 1985), Papua New Guinea (Hornabrook and Nagurney, 1976)
and amongst the Parsi community in India (Bharucha et al.,
1988). The overall prevalence of essential tremor within these
populations ranged from 305 (Rajput et al., 1984) to 1700
(Larsson and Sjogren, 1960) per 100 and increased with age. A
prevalence of between 0 (Haerer et al., 1982) and 6.7% (Bharucha
et al., 1988)) has been found amongst people over 40 years old
and between 8.37% (Larsson and Sjogren. 1960) and 12.6%
(Rautaokorpi et al., 1982) in those over 70. The age-specific
prevalence, increases with advancing age and the prevalence
among people under 30 years old is reported to be less.
(Rautakorpi et al., 1982). Only 14% of the cases of Larsson and
Sjogren, (1960) and 24% of those of Rautakorni (1978) had an age
of onset before 30 years. Similarly. the age-specific incidence
is reported to increase after the age of 49 years and reaches a
maximum (84 per 100 000) in the ninth decade (Rajput et al.,
1984).
 
 There is no consensus about the sex distribution of the
disorder and in this regard it is interesting that sex
chromosome abnormalities have been discovered in some patients
(Baughman et al., 1973). The Swedish (Larsson and Sjogren 1960)
and Finnish studies (Rautakorpi, 1978) produced female to male
ratios of 0.5 and 0.71. respectively, but the reverse was found
by Huerer et al.,  1982) in the USA (  1 for  white and 1.24 for
black populations) and Hornabrook and Nagurney (1976) in Papus
New Guinea (2.06). Rajput et al. (1984) and Bharucha et al.
(1988) did not detect any sex differences amongst their
respective American and Indian populations.
 
Relationship to other conditions
 
 Rigidity is widely acknowledged to be a useful sign
differentiating essential tremor from Parkinson's disease, it is
one of the three cardinal signs of the latter. However
several authors have reported finding rigidity in patients with
essential tremor' (Larsson and Sjogren, 1960; Salisachs. 1978;
Salisachs and Findley. 1984) and a 'pill rolling' tremor
(thought to be pathognomonic of parkinsonism) has also been
described (Larsson and Sjogren. 1960; Hornabrook and Nagurney.
1976).
 
 The possibility that essential tremor could be a forme fruste
of Parkinson's disease or that the two disorders formed the
extremes of a continuum were investigated by Cleeves et al.
(1988), but no relationship between the two diseases was
discovered, a view supported by the findings of Marttila: et al.
(1984). However, other workers (Hornabrook and Nagurney, 1976;
Barbeau and Pourcher, 1982; Roy et al., 1983; Geraghty et al.,
1985; Lou and Jankovic. 1991) provide provocative evidence to
suggest that the two conditions are related; a debate which is
far from resolved, although the weight of current evidence
suggests that the two conditions are unrelated (Pahwa and
Koller, 1993).
 
 Similarly, there have been numerous reports of an association
between essential tremor and spasmodic torticollis or other
forms of dystonia (Critchley, 1949. 1972; Couch 1976; Marsden,
1976; Baxter and Lal. 1979; Jankovic and Ford, 1983: Lou and
Jankovic, 1991). Conversely. Koller et al. (1992) excluded
patients with tremor and signs of dystonia (e.g. torticollis)
from their studies of essential tremor an approach which was
also taken by Larsson and Sjogren (1960) in their
epidemiological survey. The remaining major clinical studies of
essential tremor have all included patients with signs of
dystonia, either intentionally or otherwise, and this problem is
compounded by the observation that some patients with idiopathic
torsion dystonia may exhibit tremor as their only clinical
abnormality (Fletcher et al., 1990, 1991). There is one notable
exception: Jager and King's (1955) informative description of a
single large family in Utah with true hereditary essential
tremor.
 
 Tremors resembling essential tremor have also been documented
in a variety of neuropathic conditions including IgM
paraproteinaemic neuropathies (Smith et al., 1983,1984;
Dalakas et al., 1984; Leger et al., 1992), types I and II
hereditary motor and sensory neuropathies (Shahani et al., 1973;
Dyck, 1975; Harding and Thomas, 1980), acute and chronic
idiopathic demyelinating polyneuropathies (Thomas et al., 1969;
Matthews et al., 1970; Shahani and Young, 1978; Dalakas and
Engel, 1981) as well as a variety of other types off neuropathy
(Said et al., 1982) and diseases of the anterior horn cells
(Thomas, 1975). The mechanisms of tremor in these  conditions
are poorly understood and there has been        controversy about
whether or not there is a genetic association between the
dominant gene for hereditary motor and sensory neuropathies and
that for essential tremor (Shahani et al., 1973; Dyck, 1975;
Shahani, 1984)
 
Focal, site or task-specific tremors
 
 Another area of controversy is whether isolated tremors
affecting parts of the body other than the arms are formes
fruste of hereditary essential tremor. Instances of 'isolated'
head(Larsson and Sjogren. 1960; Marshall, 1962; Critchley. 1972;
Lou and Jankovic, 1991), tongue (Biary and Koller, 1987), voice
(Hachinski, 1975; Massey and Paulson, 1985) and jaw (Frey, 1930;
Critchley, 1949; Grossman, 1957) tremor have been described. In
addition, some task-specific tremors have been considered to be
formes fruste of hereditary essential tremor. For example,
primary writing tremor has been deemed by some authors to be a
variant of essential tremor (Rothwell et al., 1979; Kachi et
al., 1985; Koller and Martyn, 1986; Rosenbaum and Jankovic,
1988) and by others to be a variant of writer's cramp (Ravits et
al., 1985: Rosenbaum and Jankovic, 1988; Elbe et al., 1990). In
addition, it is debated whether primary orthostatic tremor is or
is not a separate entity to essential tremor (Thompson et al.,
1986; Rothwell, 1989; Britton et al., 1992a). These issues await
resolution.
 
Pharmacology
 
 The responsiveness of essential tremor to alcohol is a
characteristic but not unique feature of the condition
(Critchley, 1949,1972; Davis and Kunkle, 1951; Ashenhurst, 1973;
Sutherland et al., 1975; Findley, 1987; Koller et al., 1992) and
the percentage of patients reported to respond has varied from
42% (Findley, 1987) to 75% (Koller et al., 1992). However,
relief is temporary and tremor rebounds in an exaggerated form,
so that the need for another drink arises (Critchley, 1949).
Several reports have claimed that there is an increased
incidence of alcoholism in patients with essential tremor
(Massey and Paulson, 1978; Nasralla et al., 1982), but a
prospective study concluded that this was not significantly
different from other chronic neurological diseases or tremulous
conditions (Koller, 1983). Injections of alcohol into the
brachial artery have no ameliorating effect on tremor of that
arm (Growdon et al., 1975).
 
 Beta-adrenergic receptor blocking agents (Marshall, 1968:
Sevitt, 1971; Winkler and Young, 1971) and primidone (O'Brien et
al., 1981. Findley and Calzetti, 1982; Findley et al., 1985) are
established treatments for essential tremor, having been
subjected to randomized double-blind trials, but these drugs are
only partially effective and are associated with significant
side-effects (Koller et al,. 1986; Findley. 1987).
Phenobarbitone has been found to be significantly better than
placebo is reducing tremor amplitude but not at improving tests
of motor performance or patients' self-assessments of disability
(Findley and Cleeves, 1985). Similarly, some studies have
suggested that propranolol does not improve the functional
capabilities of patients (Foster et al., 1973; Sweet et al.,
1974; Baruzzi et al., 1983) whereas primidone does (Chakrabarti
and Pearce, 1981) Koller et al., (1986) concluded that both
propranalol and primidone facilitated eating, drinking and
writing but had no beneficial effect on the extent of
embarrassment, fine manipulative skills and motor performances
during pegboard and tapping tasks. The  mechanisms of action of
primidone and phenobarbitone are not known, but are presumed to
be within the central nervous system. The response to beta
blocking drugs was considered, in a detailed review by Findley
(1987). to be predominantly mediated by way of peripheral
beta2adrenoreceptors. However, effects within the central
nervous system or a less accessible peripheral compartment or
involving beta1-receptor sites may also be important (Young et
al., 1975; Abila et al., 1983, 1985a,b; Findley, 1987).
 
Pathophysiology
 
Post-mortem studies have failed to demonstrate a consistent
pathological substrate for essential tremor (Cestan, 1899;
Bergamasco 1907; Hassler, 1939; Mylle and van Bogaert, 1940,
1948; Herskovitz and Blackwood, 1969; Lapresle et al., 1974;
Rajput et al., 1991). Ipsilateral hemiparesis (Young, 1986),
cerebellar stroke (Dupuis et al., 1989) and stereotactic lesions
of the contralateral thalamus (Laitinen, 1965; Blacker et al.,
1968; Hirai et al., 1983) can abolish essential tremor in man.
C15O2 positron emission activation studies have demonstrated
that in patients with essential tremor there is bilateral
overactivity of the cerebellar circuitry even during rest, when
no tremor is apparent (Colebatch et al., 1990; Jenkins et al.,
1993). Furthermore, hypermetabolism of glucose within the
medulla has been detected using [18F]2-deoxyglucose and was
believed to represent overactivity of the inferior olive
(Dubinsky and Hallett, 1987).
 
 The reported frequencies of the postural component of essential
tremor to the upper limbs ranged from -4 to 12 Hz in different
subjects and are by no means diagnostic (Critchley. 1949;
Marshall, 1962; Hubble et al., 1989; Calzetti et al., 1987;
Koller et al., 1992).
 
 Electromyographic studies have shown that essential tremor is
generated by segregation of muscle activity in bursts and
different patterns have been detected in agonist/antagonist
muscle pairs. Both co-contracting and alternating patterns have
been recorded, the former more frequently (Shahani and Young,
1976; Rothwell et al., 1987). In addition 'skipping' between
these two patterns or involvement the antigravity (agonist)
muscles alone are well-established pictures (Deuschl et al.,
1987; Koller et al., 1992).
 
 Subclassification of essential tremor has been attempted using
clinical, electrophysiological and pharmacological criteria
(Findley and Gresty, 1981; Marsden et al., 1983, Deuschl et al.,
1987) but more recent studies have found support for these
proposals (Lou and Jankovic. 1991; Koller et al., 1992).
 
 The pathophysiology of essential tremor has been widely debated
but the specific neurophysiological fault remains elusive (Elbe
and Koller, 1990; Bain, 1993). The stretch reflexes, which are
of normal size, latency and duration, may be followed by an
underdamped oscillation (Rothwell et al., 1987). However, as the
severity of essential tremor worsens the phase of tremor becomes
increasingly difficult to reset by peripheral mechanical
perturbations (Britton et al., 1992b) In addition,
accelerometric studies have shown that as tremor severity
increases the averaged spectra (which display mean squared
acceleration of the frequency components against frequency)
changes from multiple small peaks of comparable magnitude
towards a single dominant peak of greater size, which may be
accompanied by harmonics. As tremor becomes more symptomatic,
the stability of the accelerometric spectral peak frequency,
measured during different manual tasks, increases and the 4-5 Hz
frequency changes seen in mild cases were reduced to ~1 Hz or
less (Bain et al., 1993b) Elble (1989) measured the attractor
dimension of essential tremor and demonstrated that it
fluctuated between limit-cycle and chaotic modes oscillation,
when tremor was respectively, symptomatic and relatively
quiescent. He concluded that essential tremor resulted from a
reduction in the functional degrees of freedom within the
involved neural pathways.
 
 Clearly, several basic but important facts about essential
tremor have not been established or are subject to controversy.
The assumption that hereditary essential tremor and the sporadic
essential tremors are the same entity has arisen insidiously
within the literature but may not be true. Isolated tremors,
other than that of the arms. and task-specific tremors may or
may not be manifestations of essential tremor. Dystonia poses
another problem because it causes tremor that is similar to that
seen in essential tremor, and could and has contaminated many
studies of the latter. This study has concentrated on defining
the core condition of hereditary essential tremor to clarify
these issues through detailed personal observation of the
clinical phenotype of inherited essential tremor.
 
Patients and methods
 
 The various components of tremor were as defined by ad hoc
committee of the Tremor Investigation Group of the
International Tremor Foundation in the following way    (Findley et
al., 1993): (i) real tremor. i.e. tremor occurring when the
muscles are not voluntarily activated and the relevant body part
is supported against gravity; (ii) tremor, i.e. tremor present
whilst voluntarily maintaining a position against gravity; (iii)
kinetic tremor, i.e. tremor during any form of movement; (iv)
task-specific tremor. i.e. appearance of kinetic tremor during
the performance of   highly specific skilled movements; (v)
intention tremor, i.e. the pronounced exacerbation of kinetic
tremor towards the end of a goal directed movement.
 
Index cases
 
 Individuals with hereditary essential tremor were
recruited from the clinics of the National Hospital for
Neurology and Neurosurgery, London, and the Havering Hospital
Trust Essex. Index cases had a family history of tremor
involving at least three generations and fulfilled the clinical
diagnostic criteria agreed by the Tremor Investigation Group
above. (Findley et al., 1993).
 
Inclusion criteria
 
(i) The presence of visible and persistent postural tremor
involving the hands or forearms which may or may not be
accompanied by kinetic tremor. The postural upper limb tremor
can be asymmetric and tremor may affect other parts of the body.
(ii) Tremor must have persisted for at least 5
years, albeit with some fluctuation in severity, but need not
produce disability.
 
Exclusion criteria
 
(i) The presence of other abnormal neurological signs with the
exception of 'cogwheeling' without rigidity and Froment's sign
which is cogwheeling induced when the contralateral limb
performed voluntary repetitive movements, a derivation of the
'signe de Froment' (Froment and Gardere, 1926).(ii) The
existence of known causes of enhanced physiological tremor (e.g.
hyperthyroidism). (iii) Concurrent or recent exposure to
tremorgenic drugs or the presence of a drug withdrawal state.
(iv) A history of neurological trauma in the 3 months prior to
the onset of tremor. (v) Clinical evidence for a psychogenic
origin of tremor. (vi) Tremor of sudden onset.
 
 Comprehensive histories were obtained from the index patients
who were re-examined and recorded on videotape using a Panasonic
VHS NV-MSlB video-recorder. Each patient  completed  a  standard
disability  questionnaire (Appendix I) and handicap assessment
form (Appendix 2) (Bain and Findley, 1993). Neurophysiological
studies were performed to exclude large fibre peripheral
neuropathies and in addition the tremors of the index patients
were studied by surface polymyography and accelerometry (Britton
et al., l992a; Bain et al., l993a).
 
Secondary cases
 
 Nixety-three first degree relatives (74.4% of those resident it
the British Isles) and 38 more distant relatives of the index
relatives were visited, interviewed and examined by one of the
authors (P.G.B.). Definite or possibly affected relatives were
videotaped and specimens of handwriting and a drawing of an
Archimedes spiral obtained from each family member. The
relatives of the index cases were then classified into three
distinct categories: (i) definitely affected, i.e. symptomatic
with obvious postural tremor and a tremulous Archimedes spiral,
fulfilling the clinical diagnostic criteria above, except that
duration of tremor could be <5 years but >2 years in some cases;
(ii) possibly affected, i.e. either asymptomatic with definite
signs (abnormal postural tremor or a tremulous spiral) or
symptomatic without definite signs; (iii) normal.
 
 The severity of postural tremor and that apparent in   Archimedes
spirals were scored using a 0-10 clinical rating scale which had
previously been assessed for both inter- and intra-rater
reliability and been shown to provide valid indices of tremor
induced disability (Bain et al.,  1993a). The tremor evident in
the spirals collected during this study were graded by three
'blind' raters and the median of their scores used in the
results. The k coefficients for the inter-rater reliability of
the scores varied from 0.63 to 0.85 (substantial to almost
perfect agreement). The severity of the postural tremors seen in
this study was scored by one trained rater (P-G.D.). It had been
hoped that the tremor apparent on each person's videotape would
be scored by three independent raters but various technical
limitations to the use of videotape arose. Consequently no
quantitative information could be obtained from them. These
difficulties and a critique of the various techniques for
assessing tremor severity have been discussed elsewhere (Bain
and Findley, 1993; Bain et al., l993a).
 
 There was still one major problem to be overcome, namely the
question of how to differentiate between essential tremor as it
presents in its early milder stages and the tremors
(physiological and enhanced physiological) which may also be
seen in healthy individuals. Even with modern neurophysiological
techniques, there is no accepted method of making this
distinction and thus the solution was inevitably pragmatic. The
scores obtained by rating postural tremor and the tremor in
spirals were used to separate essential tremor from the tremors
seen in normal individuals. In order to be considered abnormal
the severity of postural tremor or the tremor indicated in a
spiral had to be at least twice that of the 95th percentile of
that seen in healthy controls. These thresholds were determined
prior  to classification  by examining the postural tremor and
spirals of 100 healthy control subjects (age range 3-80 years).
The 95th percentile was found to be -0.1 for postural tremor and
1.0 for the tremor visible in spirals.
 
 Children under the age of 10 were examined but some of them
could not cooperate with drawing, writing and various aspects of
the examination. Consequently, they were classified as (i)
definitely affected (the mother stated that the child was
tremulous and tremor was evident on examination), (ii) possibly
affected (mother considered them to be tremulous but there were
no abnormal signs or tremor was evident on examination but the
mother was not aware that it was abnormal) or (iii) normal.
Children under the age of 15 years have been excluded from the
data on handedness. alcohol responsiveness and treatment. None
of them had been treated.
 
 The presence and extent of tremor-induced disability and
handicap were obtained by asking the index patietsts and the
definitely and possibly affected secondary cases (aged over 15
years) to complete disability (Appendix 1) and handicap
questionnaires (Appendix 2) (Bain and Findley, 1993).
 
Statistics
 
 Segregation ratios were calculated for the siblings of the
index patients (excluding the index) and the offspring of
definitely affected individuals (including those of the index
patients and their siblings). Segregation ratios were calculated
only for those relatives examined personally by P.G.B., but
confidence limits were based on all relatives, including those
not seen. The lower limit assumed that all of those stated to be
normal but not examined were normal, whilst the upperlimit
assumed that this group contained the same proportion of
definite and possible cases as was found in the examined kin but
with the possible cases counted as affected (based upon the
method used by Fletcher et al., 1990).
 
 The risks for a currently unaffected child of a parent with
hereditary essential tremor developing the disease were
calculated using Bayesian statistics with the actual segregation
ratios found in this study.
 
Results
 
 Clinical features
 
 Index patients
 
 Twenty index patients. 12 males and eight females, were
studied. The sex difference was not significant (X2 = 0.8,
P> 0.05). Seventeen were right-handed and three lefthanded. The
distributions of age, age at tremor onset (the age at which
patients were first noticed to be tremulous) and the duration of
tremor are shown in Fig. 1. The distribution of age at tremor
onset was bimodal [F(18) = 110.6, p < 0.001). The medians and
ranges of patients' ages, age at tremor onset and tremor
duration are shown in Table 1 and their cumulative ages of onset
plotted in Fig. 2.
 
 In every index patient, tremor presented in the arms; in 15
(75%) the onset was symmetrical and in five (25%) tremor was
first noticed in the dominant hand. In two patients (10%) the
upper limbs remained the only affected site but in the majority
(n = 18,90%) tremor spread to affect the legs (n = 9, 45%), head
(n = 7, 35%), voice (n = 6, 30%), tongue (n = 4, 20%), facial
muscles (those supplied by the seventh cranial nerve) (n = 3,
15%) and jaw (n = 1, 5%). Four of the patients' voice tremors
and three of the head tremors were intermittent.
 
 The most common sequence of spread was from the upper limbs to
the legs (n = 7, 35%) but in six patients (30%) tremor spread
firstly from the hands to the head, in two (10%) from the hands
to the tongue, in one (5%) from the hands to the jaw, in one
(5%) to the facial muscles (5%) and in one other (5%) to the
voice.
 
 All but one of the index patients had bilateral postural upper
limb tremors which were highly symmetrical (rated using scores
for postural tremor; correlation coefficient
r = 0.62, P < 0.01). Four patients (20%) had significant end of
movement accentuation of tremor during the finger-nosefinger
test (an intention component) and five (25%) had a mid-movement
component of kinetic tremor of a similar magnitude to their
postural tremor, but in the majority (n = l5, 75%) tremor
magnitude was diminished by movement. None of the patients had a
rest tremor when completely) relaxed. The frequencies of the
postural upper limb tremor, ranged from 4.5 to 10 Hz (mean 6.55
Hz). The electromyogram pattern in the wrist flexors and
extensors was alternating in 11 (55%), co-contracting its two
(10%), varied between alternating and co-contracting in three
(15%) and was segregated only in the wrist extensors in four
(20%).
 
 Leg tremor was always postural and symmetrical and except in
two patients, trivial. The frequency of leg tremor varied from 8
to 10Hz. One of the patients with symptomatic leg tremor had
difficulty using the pedals of his car and another was greatly
disabled: on standing up. her leg tremor would gradually
increase in amplitude so that her leg eventually gave way,
preventing her from washing up and compelling her to use a
wheelchair whenever she out. This leg tremor was not relieved by
walking and eenhanccd by fatigue. It had a frequency of 8 Hz.
 
 Various types of postural head tremor were seen. the most
common being a 'no-no' variety which occurred in six cases
(30%). This was intermittent in three patients ( l5%);
continuous in three others (15%). One patient had a 'yes-yes'
tremor. The intermittent head tremors were often
induced by talking or writing. The frequency of head tremor
varied front 5 to 8 Hz.
 
 The  facial  muscles  involved were orbicularis oculi (n = 2,
10%), orbicularis oris (n = 1, 5%) and mentalis (n = 1, 5%) and
were often activated by talking, smiling or grimacing. Voice
tremor [present in six patients (30%)] was never associated vith
dysphonia or dysarthria.
 
 Cogwheeling was detected at the wrist in three patients 15%)
but could be made to disappear in every case by getting the
patient to relax completely; in four other patients (20%)
Froment's sign was present. None of the index cases had
diminished movement of the arms whilst walking and Wartenberg's
sign was invariably negative (normal passive arm swing on
rocking the patient's shoulders)
 
Secondary cases (affected relatives)
 
 One hundred and thirty-one relatives were examined, of whom 53
(40.5%) were definitely and 18 (13.7%) possibly affected.
Fifty-five of the definite and possibly affected relatives were
right-handed, eight were left-handed and two
 
-----------------------------------------------------------
 
 
 
Table 1 Medians and ranges for age, age at tremor onset and
tremor duration for index patients and affected relatives.
 
                  Age at study   Age of onset   Tremor duration
 
                    (years)        (years)         (years)
 
                  Median Range   Median Range     Median Range
 
index patients
(n = 20)          54.0  17-78    15.0   5-52      26.5  5-58
 
Affected relatives
 
Definite cases
(n = 53)          45.0  16-77    14.5   2-65      19.5  2-72
 
Definite and
possible
cases (n = 71)    39.0  12-77    15.0   2-65      15.0   2-72
 
 
 
-----------------------------------------------------------
 
were ambidextrous. Ninety-three were first degree relatives of
whom 43 were definitely and 10 possibly affected. Of the 38 more
distant relatives 10 were definite and eight possible cases.
Amongst 14 clsildren under 15 years of age there vere six
possible cases. There were no unaffected obligate gene carriers
and no consanguinous marriages. The sex ratios (male:female) of
the secondary cases, inclusive and exclusive of possible cases
were 0.71 and 0.83, respectively. There were no significant
differences between the numbars of affected men and women
irrespective of whether possible cases were included (X2 = 0.69,
P > 0.05) or omitted (X2 = 1.53, P > 0.05). The distributions of
age, age at tremor onset and tremor duration for the secondary
cases are shown in Fig. 3 and the medians and ranges of these
details are shown in Table 1. The distribution of age at tremor
onset was bimodal [F(48) = 173, P <0.001]. The cumulative ages
at tremor onset are plotted in Fig 2.
 
Adults. Tremor presented in the upper limbs of every single
affected relative. The onset was symmetrical in 44 (83%) of the
definite cases but in eight of the remaining nine definite cases
(15.1%), tremor was first noticed in the dominant hand. Two of
these cases switched to writing with the non-dominant hand and
then swapped back to the original hand when some years later
their tremor became more symmetrical. Only one right-handed
patient first noticed tremor in his non-dominant arm.
 
 In the majority of affected relatives (66% excluding and 74,7%
including possible cases) the upper limbs remained the only
parts of the body affected by tremor. In a minority tremor was
also detected in the legs (30,2% excluding and 23.9% including
possible cases), the head (17% excluding
and 12.7% including possible cases), jaw (5.7%), tongue (3.8%),
facial muscles (3.3%) and voice (5.7%). The sequence of spread
was most commonly from the arms to the legs(26.4%) but less
often (7.6%) tremor went directly from the hands to the head.
 
 There was a high degree of symmetry for the scores for upper
limb postural tremor, irrespective of whether or not possible
cases were included (correlation coefficient (r = 0.93, P
<0.001) or excluded (r = 0.92, 0<0.001  None of the affected
relatives had rest tremor but a kinetic component (assessed in
mid-movement) of comparable severity to upper limb postural
tremor was detected in 11.8%, of definite cases and end of
movement accentuation (intention tremor) in 5,7% of those
definitely aftected.
 
 Leg tremor when present was symmetrical and usually trivial,
but in three cases (5.7%) it was problematic. To of these
individuals had marked enhancement of leg tremor standing (with
frequencies of 7.5 and 11 Hz) and when walking, particularly
when tired, In one other case amplitude of leg tremor increased
substantially when skilled manual tasks (e,g. writing) were
performed.
 
 
John Cottingham    "KNOWLEDGE is of two kinds: we know a subject,
                    or we know where we can find information upon it."
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