AMINOPHYLLINE AND ESSENTIAL TREMOR

278 DEATHS*

DETAILS OF FIVE I

I

1

I

monitored. TLI should probably be restricted to less severely affected MS patients who are less likely to be predisposed to aspiration or urosepsis. We re-emphasise that TLI is an experimental therapy and is not recommended for treatment of chronic progressive MS except as part of an approved research

protocol.

*Other clinical and necropsy information: Case l.-Pre-TLI was a smoker with labile hypertension and involvement of brainstem, cerebellum, spinal cord, cerebrum; had dysarthria. Cause of death acute myocardial infarction. Necropsy revealed extensive demyelination and moderately excessive atherosclerosis. Case 2.-Dysphagia, dysarthria, shortness of breath. Aspirated after first TLI treatment. Involvement of brainstem, cerebrum, cerebellum, spinal cord. Died from aspiration pneumonia and decubitus ulcers. Case 3.-Involvement of brainstem, cerebellum, spinal cord. Cause of death aspiration pneumonia (staphylococcal) secondary to severe brainstem involvement. Hypoxia, seizures, urinary tract infection. Extensive

demyelination at necropsy. Case 4.-Involvement of cerebrum, brainstem, cerebellum, spinal cord; dysarthria. Died from aspiration pneumonia (staphylococcal). Extensive demyelination at necropsy. Case 5.-Involvement of brainstem cerebellum; dysarthric, dysphagic. Intermittent urinary tract infections, self-catheterisations. Post-TLI had recurrent urinary tract infections, indwelling bladder catheter, bladder

Department of Neurosciences, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA

S. D. COOK R. TROIANO G. ZITO C. ROHOWSKY-KOCHAN A. SHEFFIT P. C. DOWLING

Clara Maass Medical Center, Belleville, New Jersey

C. K. DEVEREUX

SD, Devereux C, Troiano R, et al. Effecy of total lymphoid irradiation in chronic progressive multiple sclerosis. Lancet 1986; i: 1405-09. Cook SD, Devereux C, Troiano R, et al. Total lymphoid irradiation in chronic progressive multiple sclerosis: relationship between blood lymphocytes and clinical

1. Cook

2.

course. Ann Neurol 1987; 22: 634-38. 3. Devereux C, Troiano R, Zito G, et al. Effect of total lymphoid irradiation on functional

multiple sclerosis: importance of lymphopenia early after Neurology 1988; 38 (suppl 2): 32-37 4. Kaplan HS. Hodgkin’s disease. 2nd ed. Cambridge, Massachusetts: Harvard University Press, 1980: 366-41. 5. Zvaifler NJ. Fractionated total lymphoid irradiation: a promising new treatment for rheumatoid arthritis? Yes, no, maybe. Arthritis Rheum 1987; 30: 109-14. 6. Bookman MA, Longo DL, Young RC. Late complications of curative treatment in Hodgkin’s disease. JAMA 1988; 260: 680-83. 7. Hanly JG, Hassan J, Moriarty M, et al. Lymphoid irradiation in intractable rheumatoid arthritis: a double-blind, randomized study comparing 750-rad treatment with 2,000-rad treatment. Arthritis Rheum 1986, 29: 16-25. status

in chronic

treatment.

carcinoma. Cause of death unknown.

AMINOPHYLLINE AND ESSENTIAL TREMOR received TLI have died, 42-54 months post-therapy, as compared with 1 of 21 patients in the sham-irradiated group (not significant). 4 of these deaths were in severely disabled TLI patients who deteriorated to Kurtzke 8 or 9 before death (table). All were in the high lymphocyte, poor prognosis group. In contrast none of the 37 patients with mean lymphocyte counts below 850/ul in the first 3 months post-TLI (23 also on prednisone) have died, although these patients presumably had a greater immunosuppressive effect from TLI than patients with higher lymphocyte counts. In considering whether TLI might have contributed to these deaths, especially those for aspiration pneumonia (footnote to table), it is pertinent to consider the infectious complications of TLI in Hodgkin’s disease and rheumatoid arthritis. 4,5 Low rates of bacterial infection have been reported in patients receiving TLI at 4000 cGy in Hodgkin’s disease.4 Any sepsis was usually observed shortly after treatment when the effect of TLI on neutrophils and lymphocytes was at a peak.4,6 Bacterial infection and sepsis have been reported in about 20% of patients with refractive rheumatoid arthritis who have received TLI.5 These patients were generally over age 60 and had received several prior and concomitant immunosuppressive

therapies. Two possibilities

emerge. The deaths in our TLI patients may have been unrelated to TLI but an expected consequence of the severe disabilities seen in advanced MS. The life expectancy of patients with Kurtzke disability ratings of 8 and 9 is, presumably, shortened considerably because of a propensity to serious infections from aspiration, decubitus ulcers, and urosepsis. The alternative is that serious infections are more common or have a graver prognosis in a chronically ill patient with MS (or any autoimmune disease) who has been immunosuppressed by TLI or drug therapy than in a similar patient not so treated. Serious bacterial infections may be less frequently seen in Hodgkin’s disease after TLI because they are often young, and otherwise healthy, not being predisposed to urosepsis or aspiration. We cannot say which explanation is more likely. If infection after TLI has a worse prognosis in a disabled MS patient, perhaps such severe infections will be less frequent if the spleen is not radiated; TLI may cause functional hyposplenism and hyposplenism is associated with an increased risk of bacterial infection .7 We have not irradiated the spleens of our last 15 MS patients treated with TLI. These patients are now being closely

SIR,-Several drugs (clonazepam, primidone, propranolol, phenobarbitone) are prescribed for the treatment of essential tremor, but their application is limited because of side-effects.1-
Theophylline

=

=

=

279 neurotransmitters such

as noradrenaline.8 Thus theophylline may enhance inhibitory tone in central-nervous-system areas, such as the cerebellum and inferior olivary nucleus, thought to be of importance in the pathophysiology of essential tremor.9

Department of Neurology, Central Hospital of Fejer County, Szekesfehervar, Hungary *Present address.

JUDIT MALLY*

department of pharmacology, Glasgow University, Glasgow G1 2 8QQ.

1 Findley LJ. The pharmacological management of essential tremor. Clin Neuropharmacol 1986; Suppl 2: S61-75. 2 Biary N, Koller W. Kinetic predominant essential tremor: successful treatment with clonazepam. Neurology 1987; 37: 471-74. 3 Dietrichson P, Espen E. Primidon and propranolol in essential tremor: a study based on quantitative tremor recording and plasma anticonvulsant levels. Acta Nuerol Scand 1987; 75: 332-34. 4. Martinelli P, Gabellini AS, Gulli MR, Lugaresi E. Different clinical features of essential tremor: a 200-patient study. Acta Neurol Scand 1987; 75: 106-11. 5 Sasso E, Perucca E, Calzetti S. Double-blind comparison of primidone and phenobarbital m essential tremor. Neurology 1988; 38: 808-10. 6 Seyfert S, Hone A, Holl G. Primidon and essential tremor. J Neurol 1988; 235: 168-70. 7. Mally J. Effect of low dose theophylline therapy on essential tremor. New Trends Clin Neuropharmacol 1988; 1: 51-55. 8. Huber SJ, Paulson GW. Efficacy of alprazolam for essential tremor. Neurology 1988; 38: 241-43. 9. Stone TW. Physiological roles for adenosine and adenosine nervous system. Neurosciences 1981; 4: 523-55.

5-triphosphate

in the

HALOTHANE AND THE ATMOSPHERE

SiR,—Your correspondence (April 1, p 719; May 6, p 1011; May 27, p 1209) on halogenated anaesthetics and stratospheric ozone

depletion has been largely speculative. In a study we plan to publish in detail elsewhere we have done some direct laboratory measurements and report here the most important conclusions. Halogenated compounds that reach the stratosphere are damaging to the ozone layer roughly in proportion, molecule for molecule, to the number of chlorine or bromine atoms they contain. Whether or not compounds released to the troposphere ever reach the stratosphere depends on the rates of chemical destruction and physical removal from the troposphere. With halogenated anaesthetics, the most important tropospheric removal step is reaction during the day with hydroxyl (OH) radicals. Contrary to the statements of Hopkins and Albanese (May 27, p 1209), species such as halothane are not broken down significantly by photolysis in the troposphere: the onset of their ultraviolet absorption lies at shorter wavelengths than the solar radiation that penetrates to the lower atmosphere (and OH radicals are not formed by the action of sunlight on atmospheric water). Reliable rate coefficients are required for the reactions of OH with the anaesthetic agents if we are to calculate tropospheric lifetimes. We have measured rate coefficients for the reactions of OH with halothane, enflurane, isoflurane, and sevoflurane (which does not contain chlorine or bromine). We have also estimated the activation energy for the reaction, a parameter that determines the temperature dependence of reaction rates. When these new measurements are applied to a model of tropospheric chemistry, the lifetimes are about 2, 6, 5, and 1-4 years for halothane, enflurane, isoflurane, and sevoflurane, respectively. Such short lifetimes are expected for molecules containing C-H bonds, as Dr Hutton and Dr Kerr (May 6) and Dr Joyner (May 27) recognise. Transport of material through the tropopause into the stratosphere occurs on a time scale of very roughly two years. So a proportion of the anaesthetic agents does reach the stratosphere. But the potential for damage may be put in context by comparing these lifetimes with values of around 100 years for the fully halogenated chloroflurocarbons (CFCs) such as CFC-11 and CFC-12, and by comparing the annual production rates, which are about 1000 times greater for the two CFCs than for the anaesthetics. The anaesthetics will thus contribute at most a fraction of about 001 % to the total atmospheric burden of chlorine-containing species. A further potential influence on the atmosphere of the release of molecules such as the anaesthetics concerns "greenhouse" warming. Atmospheric concentrations of the anaesthetics will be much less than those of the major CFCs. Dr McCulloch points out (May 27, p 1208) that all the CFCs together produce a contribution

total greenhouse warming of less than 15% at present, and that the proportion is likely to decrease. Anaesthetics will therefore make a negligible impact on global warming. However, the one remaining piece of information needed to confirm this is the integrated infra-red absorption cross-sections of the anaesthetics in the "window" region between 800 and 1200 cm - 1. We have done these measurements and find that the integrated cross-sections range from 1400 em-2 atm-1 for halothane to 4800 em-2 atm-1 for enflurane. These values bracket those for CFC-11 and CFC-12, so that there is no anomalous spectroscopic behaviour to make the anaesthetics have an influence out of proportion with their atmospheric concentrations. to

Physical Chemistry Laboratory, University of Oxford, Oxford OX1 3QZ

A. C. A. R.

C. BROWN E. CANOSA-MAS D. PARR P. WAYNE

Shackleton Department of Anaesthetics, Southampton General Hospital

J. M.

T. PIERCE

ASSOCIATION OF CUTIS VERTICIS GYRATA WITH FRAGILE X SYNDROME AND FRAGILITY OF CHROMOSOME 12

SIR,-Cutis verticis gyrata (CVG) is an unusual conformation of scalp characterised by the presence of folds and furrows due to thickening of the corium and the subcutaneous tissue. Primary and secondary forms of CVG have been described: primary cases occur often in subjects with neuropathic features and are much more common in males than in females. 1,2 The fragile X (fra X) syndrome the

is

X-linked inherited disorder often associated with mental

an

retardation, behavioural and neurological abnormalities, and minor dysmorphic features such as an enlongated face, large ears,

prominent jaw, and macro-orchidism. Diagnosis is confirmed only if cytogenetic analysis identifies the fragile site at Xq27.3 CVG has been described in two mentally retarded male subjects, one with the fra X syndrome and the other with fragility of chromosome 10.4 At the Messina Psychiatric Hospital we have identified twenty unrelated men, aged 37-67 years, with primary CVG. All were investigated for chromosomal fragile sites by Neri and coworkers’ method.5 Five patients, three with mental retardation and two with chronic schizophrenia, proved to be positive for the fra X marker with mitoses from 4% to 14%. Moreover, in two other subjects, both with severe mental retardation and epilepsy, fragility of chromosome 12-fra (12) (q23)—was observed with 12% and 18% positive cells, respectively. On the basis of these seven cases in which primary CVG was associated with chromosomal fragile sites we believe that: (1) some cases of primary CVG may be explained by the fra X syndrome, so that CVG could represent the cutaneous marker of the syndrome in the adult; (2) this association could account, at least partly, for the higher frequency of CVG in males; and (3) cytogenetic investigation for the fragile sites should be done in patients with primary CVG associated with mental retardation, neuropsychiatric disorders, and/or dysmorphic features. Unit of Dermatology and Laboratory of Cytogenetics, OASI Institute for Research on Mental Retardation and Brain Ageing, 94018 Troina, Italy

Psychiatric Hospital,

CARMELO SCHEPIS ROSARIA PALAZZO ROSA MARIA RAGUSA

Messina

EDOARDO SPINA

Department of Haematology, Istituto Supenore Sanità, Rome

COSIMO BARLETTA

S, Butterworth T. Cutis verticis gyrata a review with report of seven new cases. Am J Ment Defic 1953; 57: 613-31. Garden JM, Robinson JK. Essential primary cutis verticis gyrata: treatment with the scalp reduction procedure. Arch Dermatol 1984; 120: 1480-83. Lubs HA A marker X chromosome Am J Hum Genet 1969; 21: 231-44. Musumeci SA, Ferri R, Stokes B, et al. Cutis verticis gyrata and chromosomal fragile sites: description of two clinical cases. 8 World Congress of the International Association for the Scientific Study of Mental Deficiency (Dublin, Ireland, Aug

1. Polan 2.

3. 4.

21-25, 1988): abstr. Sanfilippo S, Pavone L, et al. The fragile X in Sicily: survey. Am JMed Genet 1988; 30: 665-72.

5. Neri G,

an

epidemiological