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Effective treatment for essential tremor.

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LETTERS
Familial Herpes Simplex Encephalitis
Alan C. Jackson, MD,1,2 Michel Melanson, MD,1 and
John P. Rossiter, MB, PhD3
Herpes simplex encephalitis (HSE) is a sporadic encephalitis
with an incidence of about 2 to 4 cases per million population per year.1,2 The occurrence of HSE in two members of
a family has only rarely been reported.3,4 We have identified
HSE in a mother and her son within an interval of over 21
years.
A 14-year-old boy developed an illness in July 1979 with
fever, headache, nausea, confusion, and partial seizures. An
initial computed tomography head scan was normal and an
electroencephalogram showed intermittent theta and polymorphous delta activity with predominance over the right
hemisphere. Cerebrospinal fluid analysis showed 241 white
blood cells (95% lymphocytes and 5% polymorphonuclear
leukocytes) and 10 red blood cells/␮L; cerebrospinal fluid
protein was 70mg/dL and glucose 90mg/dL. Therapy was
initiated with intravenous adenosine arabinoside. He developed status epilepticus within 72 hours of admission. Electroencephalograms showed epileptiform activity over the
left temporal region that extended widely across the left
hemisphere and, later, sporadic epileptiform activity was
also noted from the right hemisphere. A repeat computed
tomography head scan showed hypodense lesions in the left
frontal and temporal lobes with mass effect and contrast
enhancement. He died after a 2-week hospital course. Postmortem examination showed hemorrhagic necrosis bilaterally in the temporal lobes. Microscopy revealed leptomeningeal and perivascular inflammatory cell infiltrates and
scattered neuronal intranuclear inclusions. Immunohistochemistry demonstrated strong labeling for herpes simplex
virus 1 antigen in multiple neurons (Fig A) and glial cells;
ultrastructural studies showed virions about 100nm in diameter consistent with herpes simplex virus.
In November 2000, his mother at age 68 developed an
illness with headache, mild aphasia, confusion, and mild
fever. She had a generalized seizure after admission to hospital and an electroencephalogram showed irregularly repetitive sharp wave and focal delta activity in the left temporal
region. A magnetic resonance imaging scan showed lesions
in the left medial temporal lobe and the insular cortex on
T2-weighted and fluid-attenuated inversion recovery
(FLAIR) sequences (see Fig B). Cerebrospinal fluid showed
173 white blood cells (100% mononuclear cells) and 326
red blood cells/per ␮L; cerebrospinal fluid protein was
97mg/dL and glucose 74mg/dL. Herpes simplex virus 1
DNA was detected in the cerebrospinal fluid with polymerase chain reaction amplification. She was treated with a 21day course of intravenous acyclovir and showed clinical improvement. She had mild residual impairment of memory
and mild aphasia, and she was able to continue to live independently.
Familial HSE has been the subject of two previous reports. The first described HSE in 2 sisters with an interval of
406
© 2002 Wiley-Liss, Inc.
Fig. (A) Temporal lobe cortex from autopsy of 14-year-old boy
showing immunoperoxidase staining for herpes simplex virus 1
antigen in neurons and neuronal processes. (B) Magnetic resonance imaging during his mother’s illness showing hyperintense
signal in the left medial temporal lobe on fluid-attenuated
inversion recovery (FLAIR) sequences. (A) Magnification
⫻430.
8 years;3 the second described HSE in 2 brothers within a
13-year interval.4 We now report fatal HSE in a 14-year-old
boy followed by HSE affecting his mother over 21 years
later, and we believe that this is the first report of HSE in
both a parent and child. In combination with the two previous reports of familial HSE, this suggests the possibility of
an increased genetic susceptibility to the occurrence of HSE
in these cases. Alternatively, strains of herpes simplex virus
with enhanced neuroinvasive or neurovirulent properties5
may be transmitted between family members or they may
share a common source, and these strains may be more likely
to cause HSE upon reactivation years later. These familial
cases raise suspicion that there are biologic factors involving
the host, the virus, or both, that favor familial occurrence of
HSE and that familial cases are not merely random occurrences.
Departments of 1Medicine, 2Microbiology and Immunology,
and 3Pathology, Queen’s University, Kingston, Ontario,
Canada
References
1. Whitley RJ, Lakeman F. Herpes simplex virus infections of the
central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis 1995;20:414 – 420.
2. Corey L, Spear PG. Infections with herpes simplex viruses.
N Engl J Med 1986;314:749 –757.
3. Koskiniemi M, Saarinen A, Klapper PE, et al. Familial herpes
encephalitis. Lancet 1995;346:1553.
4. Gazquez I, Jover A, Puig T, et al. Familial herpes encephalitis.
Lancet 1996;347:910.
5. Whitley RJ. Herpes simplex viruses. In: Knipe DM, Howley
PM, Griffin DE, et al, eds. Fields virology, 4th ed.
Philadelphia: Lippincott Williams & Wilkins, 2001:2461–
2509.
DIO 10.1002/ana.10110
Effective Treatment for Essential Tremor
Robert R. Young, MD
The study by Louis and colleagues1 of the prevalence of essential tremor (ET) is certainly important and represents an
enormous amount of work. Their statement that ET is a
disorder that “is chronic, often progressive, and disabling and
for which there are few effective therapies” is clearly true but
is more pessimistic than need be. At least one therapy for ET
is extremely effective, namely deep brain stimulation (DBS)
of the thalamus,2– 4 particularly nucleus VPLa,5 and is very
safe.5
Although ET may be 20 times more prevalent than Parkinson’s disease, the numbers of patients with ET seen in
Movement Disorders Clinics are much fewer than those figures would suggest. The number of those seriously impaired
by their tremor who reach a Deep Brain Stimulation Clinic
for consideration of surgery for their disability is much
smaller yet, certainly less than one-third of those sent for
evaluation for surgery for Parkinson’s disease.
I suspect our failure to see most of those whose tremor we
could alleviate is attributable to the concept, held by patients, their families, and their physicians, that “there are few
effective therapies” and, as their relatives have done, patients
must learn to live with the tremor. An antisurgical pessimism
obviously exists among neurologists, particularly older ones,
but I hope it can be overcome now that DBS, in the right
hands, has been shown to afford excellent relief of tremor. As
Louis and colleagues demonstrate, at least 20% of the increasing elderly population will develop ET. If they are not
aware of the benefits of DBS, a large percentage of the elderly will be needlessly handicapped by their tremor. We
need to educate our colleagues as well as family physicians
and the population at large. Most persons of any age need
not be handicapped by ET.
Movement Disorders Program, Good Samaritan Hospital,
University of Southern California, Los Angeles, CA
References
1. Louis ED, Ford B, Frucht S, et al. Risk of tremor and impairment from tremor in relatives of patients with essential tremor: a
community-based family study. Ann Neurol 2001;49:761–769.
2. Koller W, Pahwa R, Busenbark K. High-frequency unilateral
thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997;42:292–299.
3. Limousin P., Speelman JD, Gielen F, et al. Multicenter European study of thalamic stimulation in parkinsonian and essential
tremor. J Neurol Neurosurg Psychiatry 1999;66:289 –296.
4. Ondo W, Almaguer M, Jankovic J, Simpson RK. Thalamic deep
brain stimulation: comparison between unilateral and bilateral
placement. Arch Neurol 2001;58:218 –222.
5. Young RR, Dogali M. Results of 43 thalamic deep brain stimulator implants. Parkin Relat Dis 2001;7:S89.
DOI 10.1002/ana.10122
Reply
Elan D. Louis, MD, MS, Blair Ford, MD,
Steven Frucht, MD, and Ruth Ottman, PhD
Young makes the important point that deep brain stimulation is an effective treatment for essential tremor (ET) and,
as noted in our article1 and elsewhere,2 deep brain stimulation can provide relief for severe medically intractable cases.
We have found, however, that one of the major obstacles is
patient reluctance to undergo brain surgery and have a mechanical device implanted under their skin. Young also alludes to the fact that the proportion of community-dwelling
ET cases who seek medical attention is small,3 although most
have some functional disability.4 Several potential explanations have been proposed. First, the tremor is often viewed as
a constitutional idiosyncracy or an unavoidable consequence
of the normal aging process, rather than the result of a potentially treatable disease that has a cause, a well-defined natural history, and an (albeit unknown) underlying pathophysiology. Second, although it may be functionally disabling,
the disease is regarded as “benign” because it is not thought
to be associated with an increased risk of adverse outcomes,
such as morbidity or mortality. However, few data are available, and this requires further study. Finally, some people
may be reluctant to seek medical attention because of the
slow evolution of symptoms, allowing them to make
necessary-adjustments and modifications. As Young points
out, many people with ET choose to “learn to live with the
tremor” rather than seek medical or surgical treatment.
Columbia University, New York, NY
References
1. Louis ED, Ford B, Frucht S, et al. Risk of tremor and impairment from tremor in relatives of patients with essential tremor: a
community-based family study. Ann Neurol 2001;49:761–769.
2. Louis ED. Clinical practice: essential tremor. N Engl J Med
2001;345:887– 891.
3. Larsson T, Sjögren T. Essential tremor: a clinical and genetic
population study. Acta Psychiatr Neurol Scand 1960:36(suppl
144);1–176.
4. Louis ED, Barnes LF, Albert SM, et al. Correlates of functional
disability in essential tremor. Mov Disord 2001;16:914 –920.
DOI 10.1002/10123
© 2002 Wiley-Liss, Inc.
407
Spinocerebellar Ataxia Type 10 in the French
Population
Hiroto Fujigasaki, MD, PhD,1 Sandrine Tardieu,1,3
Agnès Camuzat,1 Giovanni Stevanin, PhD,1
Eric LeGuern, MD, PhD,1,3 Tohru Matsuura, MD, PhD,4
Tetsuo Ashizawa, MD, PhD,4
Alexandra Dürr, MD, PhD,1–3 and Alexis Brice, MD1–3
The autosomal dominant cerebellar ataxias are a heterogeneous group of neurodegenerative diseases with at least 15
responsible loci/genes, designated spinocerebellar ataxia
(SCA) 1 to 8, 10 to 14, 16, and 17 (Genome Database,
www.gdb.org). Mutations cause cerebellar ataxia variably associated with other signs. SCA10 is characterized by cerebellar ataxia and generalized seizures.1 The underlying mutation, a large expansion of an ATTCT repeat in intron 9 of
the SCA10 gene1 has only been found in Mexican families.2
To determine the relative frequency of SCA10 in France, we
examined the size of ATTCT repeats in index cases from
161 families with autosomal dominant cerebral ataxias excluded from all other known loci (SCA1–3, 6 – 8, 12, and
173,4), 5 patients with sporadic ataxia and epilepsy, and 5
with myoclonus and epilepsy, mostly of French origin. The
ATTCT repeat lengths were examined by polymerase chain
reaction followed by Gene Scan analysis (Applied Biosystems, Foster City, CA) and the samples (n ⫽ 24) that were
not heterozygous for the repeat length were examined by
Southern blot analysis, as described previously.1 No expansions were detected, confirming that the patients were true
homozygous for this repeat. In 109 normal controls from the
French population, repeat lengths ranged from 11 to 22
units with 72.5% heterozygosity. The distribution was unimodal and the most frequent allele had 14 repeats (Figure).
In the present study, none of 123 French families with
autosomal dominant cerebral ataxias of unknown etiology
carried this mutation. Given the number of French families
with known loci (n ⫽ 133) and those excluded in this study
(n ⫽ 123),3 SCA10 must be very rare in France (95% confidence interval: 0 –1.4%), and molecular testing may not be
useful in this population.
Fig. The lengths of SCA10 ATTCT repeat in 109 normal
controls from the French population. The distribution was
unimodal and the most frequent allele had 14 repeats.
It has been shown that the relative frequencies of SCAs
with CAG repeat expansions parallel the frequencies of large
normal alleles in a given population.4,5 However, a previous
study demonstrated that the frequency of the SCA10 allele is
similar in Mexican, Caucasian, and Japanese populations. It
is also similar in French and Mexican populations1 ( p ⬎ 0.5,
Fisher’s exact test). This suggests that the relative frequency
of this mutation is either independent of the proportion of
large normal alleles or that they are still too rare to be accurately evaluated. The mechanism of this mutation in SCA10
might therefore be different from that of CAG repeat expansions.
This work was supported by the VERUM Foundation and le Association Francaise centre les Myopathies.
1
INSERM U289, 2Fédération de Neurologie, and
Départment de Génétique, Cytogénétique et Embryologie,
Hôpital de la Salpêtrière, Paris, France, and 4Department of
Neurology, Baylor College of Medicine, Houston, TX
3
References
1. Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of
the ATTCT pentanucleotide repeat in spinocerebellar ataxia type
10. Nat Genet 2000;26:191–194.
2. Rasmussen A, Matsuura T, Ruano L, et al. Clinical and genetic
analysis of 4 Mexican families with spinocerebellar ataxia type
10. Ann Neurol 2001;50:234 –239.
3. Fujigasaki H, Martin JJ, De Deyn PP, et al. CAG repeat expansion in the TBP gene causes autosomal dominant cerebellar
ataxia. Brain 2001;124:1939 –1947.
4. Fujigasaki H, Verma IC, Camuzat A, et al. SCA12 is a rare locus
for autosomal dominant cerebellar ataxia: A study of an Indian
family. Ann Neurol 2001;49:117–121.
5. Takano H, Cancel G, Ikeuchi T, et al. Close association between
prevalences of dominantly inherited spinocerebellar ataxia with
CAG-repeat expansions and frequencies of large normal CAG
alleles in Japanese and Caucasian populations. Am J Hum Genet
1998;63:1060 –1066.
DOI 10.1002/ana.10126
Reply
Astrid Rasmussen, MD, and Elisa Alonso, MD
Spinocerebellar ataxia type 10 was identified in Mexican
families, and has so far not been described in other populations.1,2 This observation led to the hypothesis of a founder
effect in Mexican population, a speculation that has been
supported by the haplotype analysis of the ATTCT repeat
and two flanking polymorphic markers in affected and unaffected Mexican chromosomes. In that study, all the spinocerebellar ataxia (SCA) type 10 Mexican families shared a
common haplotype, which was the second most common in
normal Mexican population.3 An interesting feature is that
the affected families have no known common ancestor and
they are originary from very distant parts of the country.
This could suggest that the founder chromosome is ancient;
another question left unanswered is whether this ancestor
was of Amerindian origin or a Spaniard.
Analysis of the different SCA genes in populations has
408
© 2002 Wiley-Liss, Inc.
shown that each population has its own distribution of disease frequencies; for example, in Portuguese and Brazilian
population, SCA3 is predominant; in Cuba, SCA2 accounts
for the vast majority of patients; and in Japan, SCA6 and
DRPLA have a much higher frequency than in western
countries. The situation is not different in Mexico: of our
cohort of 54 families with autosomal dominant ataxia (177
individuals), 45% have mutations in the SCA2 gene, and the
second most common ataxia is SCA10 (14.68% of the patients). So far, no mutations in the SCA1, SCA6, SCA8,
SCA12, or DRPLA genes have been detected, and only a
small proportion of cases have mutations in the SCA3 and
SCA7 genes.4 As far as we know, the only other published
population study in Latin America is from Brazil,5 where
most people have an ethnic background that is different
from the rest of the countries in the region. It will be interesting to know the relative frequency of the ataxia mutations
in other Hispanic populations, both in Iberoamerica and in
Spain, and also to screen them for SCA10 mutations. This
should help to clarify the issue of the origin of the mutation,
and more important, to determine which genes should be
tested in a particular population, in order to optimize the
molecular diagnosis of these disorders.
A final issue is to consider the possibility of phenotypic
heterogeneity as a result of the SCA10 mutation, it remains
to analyze whether Mexican patients with other neurodegenerative, psychiatric, or convulsive disorders harbor expansions
in the SCA10 gene.
Departments of Neurogenetics and Molecular Biology, Instituto
Nacional de Neurologı́a y Neurocirugı́a Manuel Velasco
Suárez, Mexico City, Mexico
References
1. Matsuura T, Yamagata T, Burguess DL, et al. Large expansion of
the ATTCT pentanucleotide repeat in spinocerebellar ataxia type
10. Nature Genet 2000;26:191–194.
2. Rasmussen A, Matsuura T, Ruano L, et al. Clinical and genetic
analysis of four Mexican families with spinocerebellar ataxia type
10. Ann Neurol 2001;50:234 –239.
3. Ashizawa T, Matsuura T, Rasmussen A, et al. Founder effect of
the spinocerebellar ataxia type 10 mutation in the Mexican population. Am J Hum Genet 2001;69(Suppl 2):A2086.
4. Rasmussen A, Yescas P, Matsuura T, et al. Molecular diagnosis
of spinocerebellar ataxias in a Mexican population. Am J Hum
Genet 2000;67(Suppl 2):A1902.
5. Jardim LB, Silveira I, Pereira ML, et al. A survey of spinocerebellar ataxia in South Brazil— 66 new cases with MachadoJoseph disease, SCA7, SCA8, or unidentified disease-causing mutations. J Neurol 2001;248:870 – 876.
DOI 10.1002/ana.10127
Annals of Neurology
Vol 51
No 3
March 2002
409
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