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Conjugal multiple sclerosis.

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Conjugal Multiple Sclerosis
Christopher Hawkes, MD, FRCP
Prediction of conjugal pairs by chance is estimated with an
overall Canadian multiple sclerosis (MS) prevalence rate of
0.1%,1 although published rates vary from 55 to
196/100,000.2,3 The Canadian Collaborative Study Group
database has over 15,000 patients, but this represents only
half that expected from a population of approximately 30
million. The supplied crude prevalence in 13,550 spouses,
thus predicting 13.6 cases. The percentage of patients in a
present or previous partnership in this series appears high at
87.4% and does not compare to a matched population. According to 1996 Canadian census returns, 68% have been in
a marital relationship or cohabited.
A 2 to 1 female to male distribution is assumed in the
13,550 index MS cases, but actual numbers of males and
females are not supplied. The true distribution would allow
comparison with expected numbers, which in a sample of
mean age 43 years should show a near equal number of
males and females. From the assumed ratio of 2 to 1 are
derived 13 cases expected by crude prevalence compared to
23 observed, which is significant. Further compensation is
then made to allow for remaining lifetime risk of 16.3%
based on unpublished data. An arbitrary “observed” figure of
27 is derived, which is not statistically different from their
expected adjusted figure of 20. The more adjustments made,
especially to relatively small numbers, the more insecure the
Life risk and gender are not the only variables that should
be taken into account, many of which the authors mention.
Artificial overestimation of conjugal pairs includes (1) bias
from self-referral, association with lay societies, MS clinics,
or pressure groups; (2) assortative mating; and (3) earlier diagnosis, facilitated in the partner of MS cases. Conjugal rates
may be underestimated. (1) A patient disabled by MS may
find it difficult to find a partner4 and even then will be less
liable to marry for fear of future disability. Possibly only
those with less disabling MS would be able to find partners.
If mild forms of MS are less contagious, then the number of
conjugal cases will be lowered. (2) Patients with advanced
disease may be impotent or sexually inactive.4 (3) Those
married for just a few years may not have spent sufficient
time together to allow transmission of the disease (if infectious). The duration of marriage in conjugal patients is not
given, but in another series,5 there was a latent interval up to
34 years, with the majority occurring after five to 20 years of
partnership (N. P. Robertson, personal communication).
The latent period would be particularly problematic if the
MS agent had a long incubation period and transmitted inefficiently. (4) Barrier contraception may be used in the early
phase of marriage. Despite this, the 23 conjugal pairs produced 49 offspring. Whether these are distributed evenly is
not stated nor is the number of offspring in the remaining
MS index cases. (5) If MS is an infection acquired in adolescence, as suggested by Kurtzke,6 then excess conjugal pairs
would not be expected.
In human immunodeficiency virus and human T-cell leukemia virus-1 infection, transmission is more efficient from
infected male to uninfected female, but it is high to off-
© 2001 Wiley-Liss, Inc.
spring.7 If MS infectivity is comparable, there would be a
deficit of conjugal pairs where the female is first affected
prior to their relationship. The number of MS male partners
from index cases will therefore be reduced considerably if
transmissibility is inefficient from female to male.
The risk for monozygotic twin pairs is stated to be about
35% where one twin has the disease. This is almost certainly
an overestimation and based heavily on the Canadian and
British twin studies; results of the French study are not mentioned. In a review of MS twin studies,8 it was noted that
while the index of heritability was high at 0.86 ⫾ 0.3 for
Canada and 0.74 ⫾ 0.14 for Britain, it was only 0.24 ⫾
0.36 for France. The French data do not support (or exclude) a genetic basis for MS, but they are rarely quoted.
Many confounding variables are discussed by the authors,
but they are dismissed in favor of the genetic hypothesis.
Although this report is helpful, it does not eliminate the possibility of an infectious basis to MS.
Institute of Neurology, London, UK
Note Added in Proof
Since the above letter was written, 5 cases of conjugal MS
have been identified from a Sardinian database of 659 cases
giving a crude conjugal rate of 0.98%; 5 times higher than
expected by chance for that country (0.15%; Cocco E et al.
J Neurol 2001;248(suppl 2):116).
1. Ebers GC, Lee IML, Sadovnick AD, Duquette P, Canadian Collaborative Study Group. Conjugal multiple sclerosis: populationbased prevalence and recurrence risks in offspring. Ann Neurol
2. Pryse-Phillips WEM. The incidence and prevalence of multiple
sclerosis in Newfoundland and Labrador, 1960 –1984. Ann Neurol 1986;20:323–328.
3. Warren S, Warren KG. Prevalence of multiple sclerosis in Barrhead County, Alberta, Canada. Can J Neurol Sci 1992;19:
4. Rodriguez M, Siva A, Ward J, et al. Impairment, disability and
handicap in multiple sclerosis: a population-based study in Olmsted County, Minnesota. Neurology 1994;44:28 –33.
5. Robertson NP, O’Riordan JI, Chataway J, et al. Offspring recurrence rates and clinical characteristics of conjugal multiple sclerosis. Lancet 1997;349:1587–1590.
6. Kurtzke JF. Epidemiologic evidence for MS as an infection. Clin
Microbiol Rev 1993;6:382– 427.
7. Figueroa JP, Morris J, Braithwaite A, et al. Risk factors for
HTLV-1 among heterosexual STD clinic attenders. J Acquir Immune Defic Syndr Hum Retrovirol 1995;9:81– 88.
8. Hawkes CH. Twin studies in medicine—what do they tell us? Q
J Med 1997;90:311–321.
George C. Ebers, MD,1 A. D. Sadovnick, PhD, FRCP(c),2
and Pierre Duquette, FRCP(c),3 for the Canadian
Collaborative Study
Dr Hawkes wishes to make the point that our study does not
eliminate the possibility of an infectious basis to multiple
sclerosis (MS). Proof of absence is a difficult standard to attain. However, we find little if anything to suggest transmis-
sibility in the genetic epidemiology derived from a variety of
population-based studies in Canada. Dizygotic twins have
concordance as for siblings,1 the adoption study indicated
that growing up with someone destined to acquire MS put
the individual at no demonstrably greater risk unless they
were biologically related,2 the risk for half-siblings raised together was not greater than for those raised apart,3 and birth
order studies were negative4,5; in addition we could not demonstrate an increase risk to spouses.6
Dr Hawkes disagrees with some of the assumptions we
had to make. However, he does not explain why he thinks
we should compare Canadian data with French controls instead of recurrence risks in the same population from which
these conjugal pairs derived. We do not think Dr Hawkes’
arguments that we overestimated the expected rates are supported by the observed facts from this population. MS patients actually had a higher likelihood of both having spouses
and keeping them. This was somewhat contrary to our own
expectations. These findings would seem to invalidate his
first three reasons for a suggested underestimation. The
fourth is at odds with the finding that the number of offspring of MS probands differs little from that of the general
population (unpublished). We would have thought the halfsib and adoption data studies addressed his final point and in
any event do not believe this would lead to an underestimation. Finally, we have replicated the half-sib study, as we had
with the twin studies,1,7 and again find no increased risk in
sibs raised together in a second independent sample (Sadovnick and Ebers, unpublished).
Dr Hawkes’ comments illustrate that the concept of transmissibility is difficult to extinguish or eliminate, and we concede that our data do not exclude this if it occurs in only a
small subgroup of all patients. The Canadian conjugal study,
although allowing for it, does not support it. We think that
ascertainment bias favoring cases over controls supersedes in
practice any of the suggested influences in the other direction. In our opinion, data to date make nontransmissibility
the null hypothesis. We look forward to actual data from Dr
Hawkes or others which disprove it.
Radcliffe Infirmary, Oxford, UK; 2Department of Genetics,
University of British Columbia, Vancouver, British Columbia;
and 3Department of Neurology, Notre Dame Hospital,
Montreal, Quebec, Canada
1. Sadovnick AD, Armstrong H, Rice GPA, et al. A populationbased twin study of multiple sclerosis in twins: update. Ann
Neurol 1993;33:281–285.
2. Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial
aggregation in multiple sclerosis. Nature 1995;377:150 –151.
3. Sadovnick AD, Ebers GC, Dyment D, et al. Evidence for the
genetic basis of multiple sclerosis. Lancet 1996;347:1728 –1730.
4. Gaudet J, Hashimoto L, Sadovnick AD, Ebers GC. Is MS
caused by an infection or adolescence and early adulthood: a
case-control study of birth order position. Acta Neurol Scandinav 1995;91:19 –21.
5. Gaudet J, Hashimoto L, Sadovnick AD, Ebers GC. A study of
birth order and multiple sclerosis in multiplex families. Neuroepidemiology 1995;14:188 –192.
6. Ebers GC, Yee IML, Sadovnick AD, et al. Population-based
prevalence and recurrence risks in offspring. Ann Neurol 2000;
7. Ebers GC, Bulman DE, Sadovnick AD, et al. A populationbased twin study in multiple sclerosis. N Engl J Med 1986;315:
1638 –1642.
Compound Heterozygosity and Variable
Penetrance in SOD1 Amyotrophic Lateral Sclerosis
Matthew J. Parton, MRCP,1
Peter M. Andersen, MD, DMSc,2 Wendy J. Broom, BSc,1
and Christopher E. Shaw, MD1,3
We welcome the publication by Hand and colleagues,1 reporting a family with amyotrophic lateral sclerosis (ALS) heterozygous for both D90A and D96N Cu/Zn superoxide dismutase (SOD1). Their findings of compound heterozygosity
in 3 affected siblings expand our concept of the heritability
of mutant SOD1-driven ALS but also raise important practical issues.
The implications for the molecular analysis of SOD1, that
all five exons need to be sequenced, are clear; but those for
genetic counseling are more difficult to interpret. Familial
ALS is usually a dominant disorder, and collectively, penetrance is reported to be 90% by the age of 70.2 Information
on the ages at death of generations I–III in this family is
therefore required to comment confidently on the penetrance
of D96N and to predict the risk of ALS to generations V
and VI.
We are also concerned that one individual (IV:34) in this
pedigree is thought to have had sporadic ALS but could not
be genotyped. There is a 1 in 8 chance that he was heterozygous for D96N; without SOD1 haplotype data from his
spouse and offspring, we cannot be confident that this individual’s disease was not associated with mutant SOD1. Several SOD1 mutations can be dominant but may exhibit low
penetrance. Occasionally, such families demonstrate that
ALS can skip generations,3 while another 14 SOD1 mutations have been found only in apparently sporadic ALS
The pedigree of Hand and colleagues1 confirms our theory that D90A-SOD1 is recessively inherited, but their data
certainly do not exclude the possibility that D96N is a
dominant allele of variable disease penetrance, and that the
simultaneous presence of the D90A allele with D96N
greatly increases the risk of developing ALS. With approximately 100,000 unaffected D90A heterozygotes and over
70 affected D90A homozygotes of Scandinavian ancestry,
we can be confident that D90A is recessive in this population, perhaps due to a protective factor.5 Given the single
pedigree, incomplete supporting information, and lack of
haplotype data in their report, we do not yet feel assured
that D96N is truly recessive and would be reluctant to
counsel families carrying this mutation that the heterozygous state was benign.
Annals of Neurology
Vol 50
No 4
October 2001
Department of Neurology, Guy’s, King’s and St Thomas’
Medical School, and the Institute of Psychiatry, London, UK;
Department of Neurology, Umeå University Hospital, and
Institute of Clinical Neuroscience, Umeå University, Umeå,
Sweden; and 3Department of Medical and Molecular
Genetics, Guy’s Hospital, London, UK
1. Hand CK, Mayeux-Portas V, Khoris J, et al. Compound heterozygous D90A and D96N SOD1 mutations in a recessive
amyotrophic lateral sclerosis family. Ann Neurol 2001;49:
2. Strong MJ, Hudson AJ, Alvord WG. Familial amyotrophic lateral sclerosis, 1850 –1989: a statistical analysis of the world literature. Can J Neurol Sci 1991;18:45–58.
3. Suthers G, Laing N, Wilton S, et al. “Sporadic” motoneuron
disease due to familial SOD1 mutation with low penetrance.
Lancet 1994;344:1773.
4. Andersen PM, Morita MM, Brown RH. Genetics of amyotrophic lateral sclerosis: an overview. In: Brown RH, Meininger V,
Swash M, eds. Amyotrophic lateral sclerosis. London: Martin
Dunitz; 1999:223–250.
5. Al-Chalabi A, Andersen PM, Chioza B, et al. Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation
share a common founder: evidence for a linked protective factor.
Hum Mol Genet 1998;7:2045–2050.
Collette K. Hand, PhD,1 Veronique Mayeux-Portas, PhD,2
Jawad Khoris, MD,2,3 Valerie Briolotti,2
Pierre Clavelou, MD, PhD,4 William Camu, MD, PhD,2,3
and Guy A. Rouleau, MD, PhD1
In response to our study,1 Parton and colleagues raise the
interesting question of variable penetrance in SOD1 amyotrophic lateral sclerosis (ALS) mutations. In particular, they
ask if the novel SOD1 mutation we described, D96N, could
be a dominant mutation with low penetrance that increases
the risk of disease in the presence of the recessive D90A mutation.
Although we cannot exclude the possibility of an alternative mode of inheritance, we believe that within our family
the D96N mutation is recessive, which is supported by a
number of observations. Firstly, only individuals carrying
both D90A and D96N mutations are affected. Most importantly, there are 3 unaffected D96N heterozygotes of advanced age (68 to 89 years) who remain free of ALS (cases
IV:21, IV:24, and V:13; see Fig 1 in Hand et al1). Age at
onset in all affected family members was 30 to 40 years. In
addition, the disease pattern within the family is strongly
suggestive of a recessive mode as all 3 affecteds are in a single
generation with the exception of 1 individual, who we propose to be a sporadic ALS case. Finally, though not conclusive, the clinical presentation is that of the distinct, recessive
ALS phenotype.
Familial ALS is incompletely penetrant, and while we cannot exclude the possibility that these heterozygous individuals will become affected, given their late age, we feel that
this is unlikely. Age at death of the individuals in generations
I–III, as requested by Parton and colleagues, would be uninformative, particularly in the absence of any mutation data
Annals of Neurology
Vol 50
No 4
October 2001
and given that we do have this information for individuals
still alive.
As for the proposed sporadic case (IV:34), in the absence
of either mutation in his examined children, we can conclude only that (1) he was not a compound heterozygote like
the other affected family members, and (2) the haplotype
data would be uninformative. We are not in a position to
speculate whether he possessed a D96N mutation alone.
We agree that, strictly speaking, the D96N mutation
could be dominant with very low penetrance and, in the
presence of recessive D90A, increases the risk of disease.
However, in the absence of an affected individual with a heterozygous D96N mutation alone and given the presence of 3
such individuals of advanced age who remain unaffected, this
theory is unlikely to explain the disease pattern in this family. We were cautious in our interpretation of these results,
and did make the point that a D96N homozygous individual
would be necessary to prove that the mutation is recessive.
We agree that the evidence provided by a single family is
insufficient to use as a basis for future management of the
mutation, and that additional families with this mutation,
should they be identified, will lead to a clearer picture of the
mode of inheritance of this mutation.
Centre for Research in Neuroscience, McGill University, and
Montréal General Hospital Research Institute, Montréal,
Canada; 2UNCD Molecular Unit, Institute of Biology, and
Department of Neurology, Hôpital Gui de Chauliac,
Montpellier; and 4Hôpital Gabriel Montpied, ClermontFerrand, France
1. Hand CK, Mayeux-Portas V, Khoris J, et al. Compound heterozygous D90A and D96N SOD1 mutations in a recessive
ALS family. Ann Neurol 2001;49:267–271.
Electroencephalographic and Clinical Correlation
of Hyponatremia Induced During Transurethral
Resection of the Prostate
Venkata R. Reddy, MD,1
and Sreenivasa S. Moorthy, MD2
The transurethral resection of the prostate (TURP) syndrome characterized by sensorial and visual changes as well as
seizures presents with central nervous system and cardiovascular system alterations. These complications result from intravascular absorption of the irrigating fluid through the
prostatic venous plexus or perivesicular spaces.1 The most
commonly used irrigation fluid is 1.5% glycine. Hoekstra et
al.2 noted that 1 of 30 patients had altered sensorium after
TURP. Early detection of symptoms is essential to prevent
major neurological and cardiovascular complications. We
prospectively evaluated clinical and electroencephalographic
(EEG) manifestations in patients undergoing TURP to determine whether the EEG changes precede either the clinical
symptoms or changes in sodium and osmolarity levels. Ammonia levels are also measured as oxidative deamination of
glycine results in ammonia, which can cause encephalopathy2
and EEG slowing.3
After approval of the institutional board and informed
Table. TURP Syndrome and Electroencephalographic Correlations
N, V, A and C
N, GSz
V, A and C
N, V, C
Normal values: sodium, 135–145 mmol/L; ammonia, 11–35 ␮mol/L; osmolarity, 280 –305 mosm/kg.
Pre ⫽ preoperative; Peri ⫽ perioperative; S/S ⫽ symptoms and signs; N ⫽ nausea; V ⫽ visual; A and C ⫽ agitation and confusion; GSz ⫽
generalized seizure; C ⫽ confusion.
consent were obtained, 20 patients (mean age, 66.8 years)
undergoing TURP were prospectively evaluated. Surgery was
done under spinal anesthesia. Pulse oximetry, electrocardiogram, and blood pressure were monitored. EEG recordings
and measurement of sodium, ammonia, and osmolarity were
done at baseline, perioperatively, and in the recovery room.
Patients were watched for symptoms of confusion, visual
changes, or seizures.
Five patients showed slowing of the EEG; serum sodium
and ammonia levels as well as osmolarity are presented in the
In 3 patients, EEGs were slow even though there were no
significant changes in sodium, ammonia, and osmolarity levels during the perioperative period compared to the preoperative period; and 2 of these patients were symptomatic. It
is not clear why the EEG became slow despite apparently
normal laboratory findings in these patients. It has been reported that acute water intoxication with hyponatremia can
cause EEG changes that do not correlate with serum sodium
levels.4 The acutely absorbed irrigation fluid may cause neuronal dysfunction even before any significant changes in
plasma sodium levels and may be responsible for the EEG
changes. In the remaining 2 patients, it is difficult to know
the role of neuronal dysfunction secondary to early neuronal
edema because of other changes. Increased glycine level during TURP is reported to be a main factor, causing visual
symptoms by inhibiting the physiological condition of the
In conclusion, the TURP syndrome occurs when large
amounts of hypotonic bladder irrigation solution are ab-
sorbed. EEG monitoring may forewarn of the TURP syndrome, especially in patients with large vascular prostates.
Presented in part at the 119th Annual Meeting of the American
Neurological Association, San Francisco, October 11, 1994.
Departments of 1Neurology and 2Anesthesia, Indiana
University School of Medicine and Richard L. Roudebush
Veterans Administration Medical Center, Indianapolis, IN
1. Hahn RG, Ekengren JC. Patterns of irrigating fluid absorption
during transurethral resection of the prostate as indicated by ethanol. J Urol 1993;149:502–506.
2. Hoekstra PT, Kahnoski R, McCamish MA, et al. Transurethral
prostatic resection syndrome—a new perspective: encephalopathy with associated hyperammonemia. J Urol 1983;130:704 –
3. Kiloh LG, McComas AJ, Osselton JW, Upton A. Infective and
non-infective encephalopathies. In: Kiloh LG, McComas AJ, Osselton JW, Upton A, eds. Clinical electroencephalography, 4th
ed. London: Butterworths; 1981. p 180.
4. Saunders MG, Westmoreland B. The EEG in evaluation of disorders affecting the brain diffusely. Current practice of clinical
electroencephalography. New York: Raven Press; 1979. p
5. Wang JM, Creel DJ, Wong KC. Transurethral resection of prostate, serum glycine levels and ocular evoked potentials. Anesthesiology 1989;70:36 – 41.
Annals of Neurology
Vol 50
No 4
October 2001
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