CNS - GENERAL AND AUTONOMIC ABNORMALITIES

1959 Roberts GB. Fundamental defect in fibrocystic disease of the pancreas. Lancet 1959; ii: 964. [PubMed] A suggestion that autonomic abnormality could be related to the basic defect. Subsequently this was investigated and the suggestion supported by others (Mitchell I, et al. J Pediatr 1978;744-748. [PubMed] ; Davis PB et al. Pediatr Res 1978; 12:703-707. [PubMed] ; Rubin et al, J Pediatr 1963; 63:1120). Autonomic abnormalities have been the subject of a recent review (Mirakhur A. Walshaw MJ. Autonomic dysfunction in cystic fibrosis. J R Soc Med 2003; 96 Suppl 43:11-17). [PubMed] although the findings have had no practical application in the treatment of the patients.

1963 Rubin LS, Barbero GJ, Chernick WS, Sibinga MS. Pupillary reactivity as a measure of autonomic balance in cystic fibrosis. J Pediatr 1963; 63:1120-1129. [PubMed]
There was considerable interest in possible abnormalities of the autonomic nervous system considered to be in some way related to the basic defect. The authors found significant differences in the pupillary reactivity between people with CF and controls. Holzel in Manchester had found normal levels of acetyl cholinesterase in various tissues and concluded any cholinergic over-stimulation was not due to absence of the hydrolysing enzyme (Holzel A et al. Lancet 1962; i: 822-823 above). Autonomic abnormalities were later confirmed by Davies et al, (N Eng J Med 1980; 302:1453-1456 below) and more recently were reviewed by Mirakhur A et al. (J R Soc Med 2003; 96 Suppl 43:11-17). [PubMed]
Although there was considerable interest in autonomic abnormalities this knowledge does not appear to have made any contribution to either the treatment or the understanding of the basic defect. There was a later report of excessive finger wrinkling in people with CF when their fingers were immersed in warm water and this phenomenon has been related to autonomic function (Elliott, 1974 below).

1966 Rubin LS, Barbero GJ, Chernick W. Pupillary dysfunction as a concomitant of cystic fibrosis. Pediatrics 1966; 38:865-873. [PubMed]
The authors found abnormalities in response to darkness, stress and recovery from stress. They considered at the time these findings were possibly being related to the basic defect. Autonomic abnormalities were first suggested by Roberts in 1959 (above). Also Holzel et al, 1962 above; Rubin et al, 1963 above; Davies et al, NEJM 1980; 302:1453-1456 and more recently reviewed by Mirakhur A et al. (J R Soc Med 2003; 96 Suppl 43:11-17).

1962 Holzel A, Schwarz V, Torkington P, Greville Williams GE. Mucoviscidosis and the autonomic nervous system. Lancet 1962; 1:822-823. [PubMed]

Aaron Holzel (figure 3) was a paediatrician working in the University Department of Medicine in Manchester, England. He published on a wide variety of paediatric subjects including CF and started the early CF clinic in Manchester. He was also involved in early meetings concerning cystic fibrosis.
Subsequent publications by other authors also concerned possible abnormalities of the autonomic nervous system (Davis PB, Kaliner M. J Chron Dis 1983; 36:269-278; Davis PB et al. Pediatr Res 1978; 12:703-707; Mirakhur A, Walshaw MJ. J R Soc Med 2003; 96 (Suppl.43)11-17.). However, no significant abnormalities were discovered in this area which led to further understanding of the basic defect or to any form of treatment.

1970 Keating JP, Feigin RD. Increased intracranial pressure associated with probable vitamin A deficiency in cystic fibrosis. Pediatrics 1970; 46:41-46. [PubMed]
Two infants with CF aged four months had signs of raised intracranial pressure associated with vitamin A deficiency. One infant had xerophthalmia and keratomalacia; one had a cranial nerve injury with facial paralysis (also Abernathy 1976 below). Raised intracranial pressure has been described by a number of authors in young infants with CF and also in non-CF infants with vitamin A deficiency examples of which are reviewed in this paper.

1974 Elliott RB. Wrinkling of skin in cystic fibrosis. Lancet 1974; ii: 108. [PubMed]
The first report of excessive wrinkling of the skin in people with CF when soaked in tap water for three minutes. Prof. Bob Elliott was a much respected paediatrician with a major "inventor/researcher tendency"! When I visited him in New Zealand in 1990, in relationship to CF, he was keen to describe how he was developing inhaled insulin for children with diabetes mellitus!
This report of finger wrinkling caused considerable interest as the basic defect was still totally obscure (see Norman et al, 1974 below).

1974 Norman AP, Mall ML, Johns MK. Skin wrinkling in cystic fibrosis. Lancet 1974; ii: 358-359. [PubMed]
Archie Norman at Great Ormond Street confirmed marked skin wrinkling in people with CF in water (figure 10) and commented that it could be an important observation. Johns M K (J Med Biol Illus 1975; 25:205-210) suggested it was due to the excessive salt concentration which increased the water binding capacity of keratin. Later it was suggested as a test of autonomic function (Bull C, Henry JA BMJ 1977; 551-552 [PubMed]).
In the Leeds CF unit Jeanette Firth, the CF centre clinic nurse, performed the test on children with CF who were attending the unit for Comprehensive Assessments of their CF and confirmed the phenomenon, but disappointingly we found it quite unrelated to the sweat electrolyte levels or any other clinical or laboratory feature of the patient’s condition (unpublished data). Subsequently there was considerable discussion as to autonomic abnormalities in CF of which skin wrinkling is a feature (see Davies et al, 1980).

1976 Abernathy RS. Bulging fontanelle as a presenting sign in cystic fibrosis. Am J Dis Child 1976; 130:1360-1362. [PubMed]
A five month old infant whose sole problem was a bulging fontanelle was confirmed as having CF and low vitamin A levels. (Also Keating & Feigin, 1970 above; also after tetracycline administration Krewsky S. Michigan Med 1968; 67:597-598; also with nalidixic acid Drigo P et al. Pedaitr Medic Chirurg 1983; 5:583-585). Benign intracranial hypertension in infants may be unexplained and resolve spontaneously.

1977 Geller A, Gilles F, Shwachman H. Degeneration of the fasciculus gracilis in cystic fibrosis. Neurology 1977; 27:185-187. [PubMed]
Nineteen percent of 106 of the spinal cords of patients dying with CF after the age of five showed posterior column degeneration. None of the patients had been anaemic or had spinocerebellar degeneration. Nutritional, toxic or hereditary factors were considered as possibly responsible. This possibility seems to have received little attention in recent years.
Later Cavalier SJ & Gambetti P.(Neurology 1981; 31:714-718.) [PubMed] reviewed 43 autopsy cases of CF and found 66% had developed dystrophic axons; neuroaxonal dystrophy correlated with the duration of the disease. Demyelination of the fasciculus gracilis occurred in 11%. They said the neuropathology of CF resembled that of vitamin E deficiency in animals but vitamin E replacement had failed to prevent the neuropathology changes in these patients.

1980 Davis PB, Shelhamer JR, Kaliner M. Abnormal adrenergic and cholinergic sensitivity in cystic fibrosis. N Eng J Med 1980; 302:1453-1456. [PubMed]
The authors noted “abnormal responses to all these agents and conclude that there is a lesion in cystic fibrosis at or beyond the level of the autonomic receptors”. Pam Davis also suggested, somewhat prophetically, that the defect may be symptomatic of a more generalised membrane dysfunction (Davis and di Sant’Agnese Pediat Res 1980; 14:83-78) – remembering this was the year before Dr Michael Knowles demonstrated the membrane electrolyte transport abnormality (Knowles et al, 1981 below).
There had been previous suggestions that there was an abnormality of the autonomic nervous system including the finding of abnormal pupillary reactions (Rubin L S et al, 1963 above), abnormal finger skin wrinkling in water (Elliott RB, 1974 above) and even that changes of CF in the pancreas may cause a state of “autonomic dyskinesia” causing more or less persistent bronchospasm and bronchorrhoea reflex abnormal pulmonary function from the pancreatic abnormality (Ayers WB et al. 1951 above). There is a later detailed review of the autonomic manifestations (Mirakhur A, Walshaw MJ. J R Soc Med 2003; 96:11-17).

Dr Pamela Davis has been a leader in CF care and research since she trained with Dr Paul di Sant'Agnese with she combined with in many studies. She has remained in the vanguard of CF patient clinical care and scientific research since the time of her first publications with Paul di Sant'Agnese in the Seventies. Her appointment of Professor of Pediatrics, Medicine, Physiology & Biophysics and Microbiology & Molecuklar Biology at Case Western Reserve University School of Medicine, Cleveland Ohio, gives some indication of the breadth of her interests.
Her views are summarised in her chapter on Patient Care and Research in Carl Doershuk's book (Doershuk 2001 below) - "We cannot let patients pass some figurative "point of no return" because of insurance pressure or complacency. Vigorous prosecution of conventional treatment should be the order of the day. Just as we cannot let up on research to develop cures of tomorrow, so too we cannot neglect the meticulous care of the patient today". Pamela Davis considers "gene therapy still offers the best opportunity to "cure" patients with CF....it seems to me that it is likely in the next five years that nontoxic gene therapy approaches will come to clinical trial that will impact on the electro physiology of the airway epithelium, demonstrate gene transfer unequivocally, and correct some of the downstream manifestations of CF in the airways. It may require additional effort and time to produce high level, long lasting correction but once the principle is established this reduces to a technical problem".
In 2006 Pamela Davis received the Paul di Sant'Agnese Award of the CF Foundation

1995 Ghosal S, Taylor CJ, Pickering M, McGraw J, Beckles-Wilson, Wales JKH. Disproportionate head growth retardation in cystic fibrosis. Arch Dis Child 1995; 72:150-152. [PubMed]
Fifty children with CF (18 diagnosed with meconium ileus, four by post natal screening, 30 by clinical diagnosis) were followed over four years. The length SD scores improved from -1.24 at birth to -0.15 at four years and the weight SD scores from -1.37 at 6 months to -0.53 at four years. In contrast the head circumference SD score reached a plateau of -1.0 from the age of 1.5 to four years and remained significantly low throughout the four years of measurement being -1.05 at four years. (also Lloyd-Still JD et al, Pediatrics 1974; 54:306-311 - "malnutrition in infancy can affect intellectual development in the first five years").
This was the first report that the head circumference of children with CF may be slightly smaller than expected. The high proportion of infants with meconium ileus (34%) in the series probably was due to Sheffield Children’s Hospital being a regional centre for neonatal surgery. The authors suggested that the data may support the expression of CFTR in the choroid plexus and ependyma. There is very little in the literature on head circumference in CF although in the Wisconsin screening data on cognitive score index (CSI) – “the highest proportion of CSI scores >84 occurred in the control <300E group (41%). Patients in this group also had the lowest mean head circumference z-scores at diagnosis” (Koscik RL et al. J Pediatr 2005; 147(3 Suppl):S51-6). A further study of screened CF infants from Sheffield confirmed that head growth appeared to lag behind somatic growth supporting the functional expression of CFTR in the brain (Ghosal S et al. Arch Dis Child 1996; 75:191-193). [PubMed]

1996 Bikangaga P, Canny GJ. Benign intracranial hypertension in infants with cystic fibrosis. Arch Pediatr Adolesc Med 1996; 150:551-552. [PubMed]
Four of 53 (7.7%) newly diagnosed infants with CF in Toronto developed transient benign raised intracranial pressure during their initial treatment. This is an apparently benign occurrence according to previous reports (Roach ES, Sinai SH. Clin Pediatr 1989; 27:371). Vitamin A deficiency has been described as a cause (Abernathy RS. AJDC 1976; 130:1360-1362 above) also systemic steroid withdrawal. Catch up growth after severe malnutrition has also been implicated but many cases are unexplained. The complication has also been described with tetracycline antibiotics since the Sixties.

2000 Needleman JP, Panitch HB, Bierbrauer KS, Schidlow DV. Chiari type I malformation in children and adolescents with cystic fibrosis. Pediatr Pulmonol 2000; 30:490-492). [PubMed]
Chiari type I malformation is characterized by herniation of the cerebellar tonsils through the foramen magnum (figure 16).
Five children and adolescents with CF in whom Chiari type I malformations were diagnosed had neurological problems including swallowing dysfunction, syncopal episodes, numbness of extremities, recurrent vomiting, and headaches.
The authors suggest that Chiari type I malformation is more common in CF than in the general population and advise should be included in the differential diagnosis of unexplained neurological complaints in people with CF.

This is a previously unreported and serious neurological complication found in 5 of 400 patients with CF. An important complication of which many paediatricians will have heard of in relation to spina bifida and hydrocephalus but not associated with CF. Further 2 infants with CF and the Chiari type 1 malformation were reported in 2003 (Rakheja D et al. Pediatr Develop Path 2003; 6:88-93. [PubMed]. The authors commented that the chances of the association occurring by chance was one in 7,500,000 so it was likely that there was some relationship.

Also neurological complications relatively common after lung transplantations (Goldstein et al, 2000)below). [PubMed]

2000 Goldstein AB, Goldstein LS, Perl MK, Haug MT, Arroliga AC, Stillwell PC. Cystic fibrosis patients with and without central nervous system complications following lung transplantation. Pediatr Pulmonol 2000; 30:203-206. [PubMed]
Eleven of 21 patients (52%) with CF had CNS events after lung transplantation: eight had seizures, five severe headaches, three had strokes, and one had a confusional episode. The authors could not identify any predictive risk factors but considered cyclosporine toxicity to be the major cause of the CNS complications. Despite the high rate of CNS events, the overall prognosis for these patients was good, and their 6-month survival was not affected.

A surprisingly high percentage of people with CF have neurological problems after lung transplantation. CNS complications are not common in CF but Arnold-Chiari malformations have been reported (Needleman JP et al. Pediatr Pulmonol 2000; 30:490 above). [PubMed]

2003 Mirakhur A. Walshaw MJ. Autonomic dysfunction in cystic fibrosis. J R Soc Med 2003; 96 Suppl 43:11-17. [PubMed]
This a useful review of the various work on the autonomic system in CF which has received attention over the years.

2004 Koscik RL. Farrell PM. Kosorok MR. Zaremba KM. Laxova A. Lai HC. Douglas JA. Rock MJ. Splaingard ML. Cognitive function of children with cystic fibrosis: deleterious effect of early malnutrition. Pediatrics 2004; 113:1549-1558. [PubMed]
The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. Cognitive assessment data were obtained for 89 CF patients (aged 7.3-17 years) during routine clinic visits. Patients had been enrolled in either the screened (N = 42) or traditional diagnosis (control) group (N = 47) of the Wisconsin CF Neonatal Screening Project. Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.

This was an important study from the Wisconsin screening group adding further evidence of the need for neonatal screening and of great importance of adequate nutritional management once diagnosed by neonatal screening.

2006 Rao DS. Infeld MD. Stern RC. Chelimsky TC. Cough-induced hemiplegic migraine with impaired consciousness in cystic fibrosis. Pediatr Pulmonol 2006; 41:171-176. [PubMed]
The coughing paroxysms of patients with cystic fibrosis may occasion neurological symptoms. Although cough syncope is well-known, and is associated with headache and paralysis, a migrainous mechanism has not been reported. We reviewed the medical records, autonomic testing results, and responses to treatment in two cystic fibrosis patients with similar presentations of cough-induced impairment of consciousness followed by headache and paralysis. A 24-year-old woman and an unrelated 38-year-old man, both with cystic fibrosis, developed post-tussive neurologic deficits. Both patients reported infrequent dramatic spells, always preceded by major hemoptysis, and associated with left-sided paralysis, transient blindness, nausea, and severe pulsating headaches. Autonomic testing demonstrated only postural tachycardia and a near-vasodepressor episode in the woman, and mild, generalized sympathetic dysfunction in the man. Treatment for presumptive migraine with aura with verapamil nearly eradicated symptoms in both patients. Discontinuation of verapamil in the woman was associated with symptom recurrence and a stroke, with significant persistent residual left hemiparesis. In conclusion, cough-induced neurologic deficits were previously reported with cystic fibrosis, without clear understanding of the mechanism of impairment of consciousness. Based on the hemiparesis, nausea, and throbbing headache, which repeatedly followed the events in both patients, and based on the response to verapamil, we hypothesize a migrainous mechanism in both of our patients. The pathophysiology that links the hemoptysis to the spells deserves further investigation.

Another type of neurological complication resulting from pulmonary problems in people with CF.

2007 Basu AP. Kumar P. Devlin AM. O'Brien CJ. Cystic fibrosis presenting with bilateral facial palsy. Eur J Paediatr Neurol 2007; 11:240-242. [PubMed]
A 15-week old male infant presented with bilateral lower motor neuron facial palsy of unknown cause. Subsequently his growth deteriorated and he developed progressively worsening cough and wheeze. A diagnosis of cystic fibrosis was confirmed and hypovitaminosis A detected. Improvement of the facial palsy was noted following standard management of cystic fibrosis including vitamin A supplementation.

Presentations due to the manifestations of vitamin deficiency, particularly of vitamin A, are well documented but this is not reported previously.

2009 Berk DR. Ciliberto HM. Sweet SC. Ferkol TW. Bayliss SJ. Aquagenic wrinkling of the palms in cystic fibrosis: comparison with controls and genotype-phenotype correlations. Arch Dermatol 2009; 145:1296-1299.
The biggest article so far on wrinkling confirms the association between aquagenic wrinkling of the palms and CF. Among patients with CF, greater AWP occurs in those who are homozygous for the DeltaF508 mutation. Also described as a reaction to tobramycin in a person with CF [PubMed]