Second edition

08.qxd 3/10/08 9:38 AM Page 378
378 Neurodegenerative and movement disorders
Clinical features
Although the range in age of onset is wide, from the first to
the ninth decades of life, most patients experience the
onset of tremor during the fifth decade.
Clinically speaking (Bain et al. 1994; Critchley 1949;
Koller et al. 1994; Lou and Jankovic 1991; Martinelli et al.
1987), in the vast majority of cases, the tremor first
becomes evident in the hand, generally bilaterally; only in a
small minority is the onset unilateral. The tremor, at least
initially, is fine, ranging in frequency from 4 to 8cps, and
postural, being most evident when the hands are held outstretched
with the fingers spread. In most cases, over time,
the tremor also becomes apparent elsewhere, including, in
decreasing order of frequency, the head, the voice, the
chin, and, in a small minority, the feet. Head tremor is generally
of the ‘no-no’ type (Bain et al. 1994) with a trembling
oscillation of the head from side to side. Involvement of
the voice may impart a quavering quality to the patients’
speech (Ardran et al. 1966). Recent work (Benito-Leon
et al. 2006) indicates that patients may also display some
cognitive deficits, but these are quite mild and of questionable
clinical importance.
Course
In most cases the course is characterized by progressive
worsening to a certain plateau, which may persist for years
or decades, after which there may be further progression.
As the tremor worsens, it characteristically becomes of
greater amplitude and slower frequency.
Etiology
Although sporadic cases do occur, both family and twin
studies (Bain et al. 1994; Lorenz et al. 2004; Tanner et al.
2001) indicate that essential tremor is, in most cases, inherited,
most likely on an autosomal dominant basis.
Although the genetic basis remains obscure, in some families
linkage has been found to sites on chromosomes 2, 3,
and 6 (Shatunov et al. 2006).
Although routine pathologic studies have been
unremarkable (Rajput et al. 2004), recent work has
demonstrated some interesting findings (Louis et al. 2005,
2006a,b). Lewy bodies have been found in brainstem
nuclei, most especially the locus ceruleus; furthermore,
within the cerebellum, Purkinje cell loss has been noted,
with, in surviving Purkinje cells, torpedoes, or massive collections
of disoriented neurofilaments. Although speculative,
these seemingly disparate findings may be reconciled
as contributing to a final common pathway of reduced
inhibitory output of the Purkinje cell layer. The locus
ceruleus has massive stimulatory projections to the
Purkinje cell layer, and with dysfunction of the locus
ceruleus, and loss of this stimulation, Purkinje cell output
would fall. A similar loss of output from the Purkinje cell
layer would also, of course, occur with loss or damage to
the Purkinje cells themselves. If these findings are replicated,
and if this speculation is correct, then it may well be
that essential tremor represents a syndrome composed of
two or more inherited disorders causing pathology either
in brainstem nuclei or in the cerebellum.
Differential diagnosis
Essential tremor is a postural tremor and, as discussed
in Section 3.1, this must be distinguished from rest and
intention tremors. Once it is clear that the patient does
have a postural tremor, the differential may be pursued as
outlined in Section 3.1, with special attention given to
medication-induced tremors (e.g., sympathomimetics or
caffeine), alcohol or sedative/hypnotic withdrawal, and
hyperthyroidism.
Treatment
A large number of medications are effective in essential
tremor. Primidone (Koller and Royse 1986) and propranolol
(Winkler and Young 1974) are the mainstays;
propranolol may be given in doses from 80 to 240 mg/day,
and primidone from 25 to 750 mg/day. Alternatives
include gabapentin (Gironell et al. 1999; Ondo et al. 2000),
in doses from 1200 to 3600 mg/day, and topiramate
(Connor 2002; Ondo et al. 2006), from 100 to 400 mg/day.
Alprazolam is also effective (Gunal et al. 2000), but given
the high risk of physiologic dependence, this should probably
be held in reserve. Regardless of which medication is
used, one should start at a low dose and increase gradually,
looking for the lowest effective dose. Another ‘medication’,
which many patients will already have discovered on their
own, is alcohol (Growdon et al. 1975), which, for obvious
reasons, cannot be recommended. In severe, treatmentresistant
cases, consideration may be given to deep brain
stimulation of the thalamus (Sydow et al. 2003).
8.33 HYPEREKPLEXIA
Hyperekplexia, also known as hyperexplexia or ‘startle disease’,
is a rare disorder characterized by a pathologic startle
response.
Clinical features
Hyperekplexia occurs in two varieties, namely the major
form and the minor form, and these differ both in age of
onset and in clinical symptomatology (Andermann et al.
1980; Kirsten and Silfverskiold 1958; Ryan et al. 1992;
Suhren et al. 1966; Tijssen et al. 1995).