CNS – General and Autonomic

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; 63:1120-1129. below).

–   Autonomic abnormalities have been the subject of a 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. below).

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 hands 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 related to the basic defect. Autonomic abnormalities were first suggested by Roberts in 1959 (above). Also Holzel et al, 1962 below; 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 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 first 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 also had xerophthalmia and keratomalacia; one had a cranial nerve injury with facial paralysis (also see 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. Professor 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 2) 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 many 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 described after tetracycline administration (Krevsky S. Mich Med 1968; 67:597-598. [PubMed]) also with nalidixic acid (Drigo P et al. Pediatr Med Chir 1983; 5:583-585.[PubMed]). 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 considered 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]

Pamela Davies

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 whom she combined 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 & Molecular 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 N, Wales JKH. Disproportionate head growth retardation in cystic fibrosis. Arch Dis Child 1995; 72:150-152. [PubMed]

Shomik Ghosal

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.[PubMed]– “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 low vitamin E (<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. [PubMed]). 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; 27:371-373.[PubMed]). 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 .
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]
After a detailed review of autonomic functions the authors concluded that autonomic dysfunction is a well-documented finding in several chronic diseases. Pharmacological studies in the early 1980s have indicated that it may also exist in CF. Preliminary data using power spectral analysis have demonstrated abnormalities in the cardiovascular system. It is known that there are pupillary reaction abnormalites and an autonomic neuropathy in a group of adult CF patients on the basis of abnormal heart variability which correlates with increasing disease severity.  Thus when considering CF as a multisystem disease, autonomic dysfunction should be included.

–   This a useful review of the previous work on the autonomic nervous system.

2004 Koscik RL, Farrell PM, Kosorok MR, Samurai 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. The authors 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, the authors 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 most comprehensive article so far on finger 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 – not previously noted. Also described as a reaction to tobramycin in a person with CF [PubMed]

2011 Patel AJ, Raol VH, Jea A. Rare association between cystic fibrosis, Chiari I malformation, and hydrocephalus in a baby: a case report and review of the literature. J Med Case Reports [Electronic Resource] 2011; 5:366.[PubMed]
The ninth case of a baby with cystic fibrosis and Chiari I malformation, in this case in a 10-month-old, full-term Caucasian baby boy. There was developmental delay, macrocephaly, bulging anterior fontanelle, and papilledema. An MRI scan demonstrated an extensive Chiari I malformation with effacement of the fourth ventricle, obliteration of the outlets of the fourth ventricle and triventricular hydrocephalus without aqueductal stenosis. A ventriculoperitoneal shunt was inserted.

The authors suggest that the cystic fibrosis transmembrane conductance regulator gene may play a previously unrecognized role in central nervous system development; alternatively, this central nervous system abnormality may have been acquired due to constant valsalva from recurrent coughing or wheezing or metabolic and electrolyte imbalances that occur characteristically in cystic fibrosis.

See also Needleman JP et al. Pediatr Pulmonol 2000; 30:490-492. [PubMed]; also this entry in year 2000 section for illustrations of example of the Arnold Chiari malformation.

2011 Obeid M, Price J, Sun L, Scantlebury MH, Overby P, Sidhu R, Chiriboga CA, Quittell LM. Facial palsy and idiopathic intracranial hypertension in twins with cystic fibrosis and hypovitaminosis A. Pediatr Neurol 2011; 44:150-152. [PubMed]
10-week-old monozygotic twins, diagnosed with cystic fibrosis by newborn screening, developed facial palsy and increased intracranial pressure. Cranial imaging and cerebrospinal fluid analysis produced normal results. Levels of serum vitamin A were below the normal range. Low levels of vitamin A are associated with facial nerve paralysis, and are at least partly implicated in the development of increased intracranial pressure in infants with cystic fibrosis.

–   Facial palsy is a well documented as associated with low vitamin A levels in CF infants (Keating JP, Feigin RD. Increased intracranial pressure associated with probable vitamin A deficiency in cystic fibrosis. Pediatrics 1970; 46:41-46.[PubMed]); Silman JS et al. Arch Otolarygol 1985; 111:822-825. [PubMed]) ;Cameron C et al. J Cyst Fibros 2007; 6:241-243 [PubMed]); Basu AP et al. Eur J Paediatr Neurol 2007; 11:240-242. [PubMed]).

2013 Chakrabarty B. Kabra SK. Gulati S. Toteja GS. Lodha R. Kabra M. Pandey RM. Srivastava A. Peripheral neuropathy in cystic fibrosis: a prevalence study. J Cyst Fibros 2013; 12:754-760. [PubMed]
Information on peripheral neuropathy in children with cystic fibrosis is scanty. The aetiology can be multifactorial (micronutrient deficiency, chronic hypoxia, impaired glucose tolerance, immunological, vasculopathic, critical illness).

Forty five children with CF aged 1-18 years on vitamin E supplementation for at least 6 months underwent detailed neurological examination, serum vitamin E, vitamin B12, folate, copper levels and detailed nerve conduction studies. The mean age of the study population was 8.35 years (+4.9 years) with 62.2% being males. Overall 22 out of 45 (48.88%,CI: 33.7-64.2) had electrophysiological evidence of peripheral neuropathy which was predominantly axonal (86.4%), sensory (50%), and polyneuropathy (95.45%).

There was no significant association between status of serum micronutrients and electrophysiological evidence of peripheral neuropathy. The authors concluded that patients with CF have electrophysiological evidence of peripheral neuropathy (predominantly axonal, sensory and polyneuropathy). There is significant association of higher chronological age with occurrence of peripheral neuropathy.

–   It is interesting that there was no significant association with the levels of micronutrients. There is some evidence that there is an intrinsic neurological abnormality as part of the abnormality of CFTR. See also Reznikov LR et al, 2013 re. Neuropathy in CFTR deficient pigs [PubMed]) and El-Salem K et al, 2010 [PubMed].

2014 Marcorelles P. Friocourt G. Uguen A. Lede F. Ferec C. Laquerriere A. Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain: Comparative Immunohistochemical Study between Patients with Normal and Mutated CFTR. J Histochem Cytochem 2014; 62:791-801.[PubMed].
Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein has recently been shown to be expressed in the human adult central nervous system (CNS). As CFTR expression has also been documented during embryonic development in several organs, such as the respiratory tract, the intestine and the male reproductive system, suggesting a possible role during development the authors decided to investigate the expression of CFTR in the human developing CNS. In addition, as some, although rare, neurological symptoms have been reported in patients with CF, they compared the expression of normal and mutated CFTR at several fetal stages. Immunohistochemistry was performed on brain and spinal cord samples of fetuses between 13 and 40 weeks of gestation and compared with five patients with CF of similar ages.
This study showed that CFTR is only expressed in neurones and has an early and widespread distribution during development. Although they did not observe any cerebral abnormality in patients with CF, they observed a slight delay in the maturation of several brain structures. They also observed different expression and localisation of CFTR depending on the brain structure or the cell maturation stage.
Their findings, along with a literature review on the neurological phenotypes of patients with CF, suggest that this gene may play previously unsuspected roles in neuronal maturation or function.

–   A number of neurological conditions have been described in people with CF; also some slight reduction in head circumference of CF infants has been reported (please see Topics – CNS section for more details).

2016 Demir SO; Atici S; Akkoc G; Yakut N; Ikizoglu NB; Eralp EE; Soysal A; Bakir M. Neurologic Adverse Events Associated with Voriconazole Therapy: Report of Two Pediatric Cases. Case Reports Infectious Diseases. 2016:3989070, 2016. [PubMed]
The current report presents two cases, one a 9-year-old boy and the other a 17-year-old girl, who experienced neurologic side effects associated with voriconazole therapy. The first case was a 9-year-old boy with cystic fibrosis and invasive aspergillosis that developed photophobia, altered colour sensation, and fearful visual hallucination. The second case was a 17-year-old girl with cystic fibrosis and allergic bronchopulmonary aspergillosis, and she experienced photophobia, fatigue, impaired concentration, and insomnia, when the dose of voriconazole therapy was increased from 12mg/kg/day to 16mg/kg/day. The complaints of the two patients disappeared after discontinuation of voriconazole therapy. In addition, although serum voriconazole concentration was not measured in the present cases, therapeutic drug monitoring for voriconazole seems to be critically important in preventing neurologic side effects in pediatric patients.

2016 Durham SH; Garza KB; Eiland LS.  Relationship between vancomycin dosage and serum trough vancomycin concentrations in pediatric patients with cystic fibrosis. American Journal of Health-System Pharmacy. 73(13):969-74, 2016 Jul 1. [PubMed]
The association between vancomycin dosage and serum trough vancomycin concentrations in pediatric patients with cystic fibrosis (CF) was examined. A study of hospital admissions involving pediatric patients with CF revealed no significant correlation, when all admissions were considered, between the initial or final vancomycin dosage regimen and the corresponding serum trough vancomycin concentration. Both correlations were significant for the subgroup of admissions representing patients who were at least 12 years old.

2016 Khanna AR; Coumans JV.  Spontaneous Improvement of Chiari I Malformation and Syringomyelia in a Patient With Cystic Fibrosis: Case Report.  Neurosurgery. 78(2):E305-8, 2016 Feb. [PubMed]
Syringomyelia is highly associated with Chiari I malformation, but the pathophysiologic mechanism of syrinx formation and its relation to downward cerebellar tonsillar displacement remains elusive. Cough, Valsalva maneuver, and other physiological strains transiently exacerbate the clinical symptoms of these conditions, exert profound effects on the flow dynamics across the craniospinal junction, and are thought to play an important role in the pathogenesis of syringomyelia.A patient with cystic fibrosis who presented during an exacerbation of bronchiectasis and was found to have a Chiari I malformation with associated syringomyelia. Eight months later, when the patient had returned to baseline pulmonary status, repeat imaging showed interval improvement in both the size of the syrinx and descent of cerebellar tonsils.The authors concluded this rare case of spontaneous improvement of syringomyelia and Chiari I malformation attributable to relief from chronic cough offers interesting insight into the mechanism of these disorders.

– This was first reported in CF by Needleman in 2000 and is a 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. Two 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]) and other described in CNS Topics section.

Stafler P, Mei-Zahav M, Wilschanski M, Mussaffi H, Efrati O, Lavie M, Shoseyov D, Cohen-Cymberknoh M, Gur M, Bentur L, Livnat G, Tarshish Y, Huang L, Jackson F, Edwards J, Fligor B, Wilkins A, Uluer A, Sawicki G, Kenna M.  Risk Factors for Hearing Loss in Patients with Cystic Fibrosis.  J Am Acad Audiol. 2016 Jan;27(1):6-12. doi: 10.3766/jaaa.14104. [PubMed]

A retrospective study of audiometric results and medication information in a cohort of patients with CF.  Records of 178 CF patients seen at Boston Children’s Hospital for audiometric testing from 2007 to 2010 were reviewed. Mean age of patients was 18 yr (standard deviation = 10 yr), and 98 (55%) of the patients were female.  Audiometric results, medications, and hospitalisations were recorded. Multivariable logistic regression was used to evaluate the association between SNHL and the number of hospitalisations and chronic antibiotic use in the year prior to the patients’ audiometry.In this sample, 37/178 (21%) patients had sensori-neuronal hearing loss (SNHL). Twenty-nine (78%) of the 37 patients had bilateral SNHL and 8 (22%) had unilateral SNHL. Across all age groups, the majority of patients had a bilateral hearing loss (HL). A multivariable model showed that older age and more frequent hospitalisations were associated with SNHL. The number of courses of chronic antibiotics in the year prior to audiometric testing was not correlated with rate of HL.The findings suggests that age and frequency of hospitalisations are key predictors of HL development.

The authors suggest that increased awareness and regular screening for SNHL should be included in the routine care of CF patients, particularly those at the highest risk.

[See also ENT topic]

Reznikov LR. Cystic Fibrosis and the Nervous System. [Review] Chest. 151(5):1147-1155, 2017 May [Pubmed]

     Leah Reznikov

Although defective anion transfer across epithelial cells is accepted as the basic defect in CF, many of the features observed in people with CF and organs affected by CF are modulated by the nervous system. This is of interest because CFTR expression has been reported in both the peripheral and central nervous systems, and it is well known that the transport of anions, such as chloride, greatly modulates neuronal excitability. Thus it is predicted that in CF, lack of CFTR in the nervous system affects neuronal function. Consistent with this prediction, several nervous system abnormalities and nervous system disorders have been described in people with CF and in animal models of CF. The goal of this special feature article is to highlight the expression and function of CFTR in the nervous system. Special emphasis is placed on nervous system abnormalities described in people with CF and in animal models of CF. Finally, features of CF that may be modulated by or attributed to faulty nervous system function are discussed.

Dr. Leah Reznikov is Assistant Professor in the Department Physiological Sciences at the University of Florida College of Veterinary Medicine. Her interests are centered on the interface of the nervous system and the airways.

–  A comprehensive review of the CNS abnormalities in people with CF. See CNS in Topics section of this history for further details.

2016 Lee AL; Rawlings S; Bennett KA; Armstrong D. Pain and its clinical associations in individuals with cystic fibrosis: A systematic review.  Chron Resp Dis 2016; 13(2):102-17. [PubMed]
The pooled prevalence of pain in adults with CF was 77% (95% confidence interval (CI): 57%-92%) and in children was 42% (95% CI: 0%-91%). Common regions of pain included back, abdomen, chest and limbs. In children and adults, pain was associated with a poorer quality of life (QOL) and significant interference with treatments. Pain is a common problem in both children and adults with CF. It has negative clinical associations with QOL and the ability to successfully undertake treatment.

Schneider EK, McQuade RM, Carbone VC, Reyes-Ortega F, Wilson JW, Button B, Saito A, Poole DP, Hoyer D, Li J, Velkov T.  The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites.  ERJ Open Res. 2018 Mar 13;4(1). pii: 00127-2017. doi: 10.1183/23120541.00127-2017. eCollection  2018 Jan. Free PMC Article   [Pubmed]

   Elena K Schneider

Ivacaftor-lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators. The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand binding assays. Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT_2C receptor (pK_i=6.06±0.03),β₃-adrenergic receptor (pK_i=5.71±0.07), δ-opioid receptor (pK_i=5.59±0.06) and the dopamine transporter (pK_i=5.50±0.20); iva-M1 displayed significant affinity to the 5-HT_2C receptor (pK_i=5.81±0.04) and the muscarinic M3 receptor (pK_i=5.70±0.10); iva-M6 displayed significant affinity to the 5-HT_2A receptor (pK_i=7.33±0.05). The in vivo central nervous system activity of ivacaftor (40 mg·kg^-1 intraperitoneally for 21 days) was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s), similarly to fluoxetine (33.8±11.0 s), and increased climbing/swimming activity (181.5±9.2 s). In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6 versusfluoxetine 57.9±9.5) and total distance travelled (ivacaftor 120.6±16.8 cm versus fluoxetine 84.5±16.0 cm) in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor-lumacaftor resulted in significant improvements in quality of life (including anxiety) in all five domains of the AweScoreCF questionnaire (p=0.092-0.096). Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood.

– For those (like this writer) unfamiliar with the Forced Swim test. In this assay mice are placed in a cylinder filled with water from which they cannot escape. After a few minutes the mice will stop trying to escape and will simply float in the water, only making swimming movements sufficient to stay afloat. This immobility response has been interpreted as a “depressed” state and research has shown that immobility is decreased by antidepressant drugs like imipramine (Tofranil, a tricyclic) and fluoxetine (Prozac, a selective serotonin reuptake inhibitor), but not drugs that belong to other therapeutic classifications (e.g. antianxiety drugs). Thus, this preclinical behavioral assay has a high reliability for identifying drugs that have antidepressant properties in humans and it can be used to understand the similarities and differences among the various drugs that have been and are currently being developed for the treatment of depression.

– Evidence that ivacaftor has a definite effect on the central nervous system.

Dr Elena Katharine Schneider (figure) is a research Fellow in Microbiology at Monash University

Bhaswati Roy, Marlyn S Woo, Susana Vacas, Patricia Eshaghian, Adupa P Rao, Rajesh Kumar.  Regional brain tissue changes in patients with cystic fibrosis. J Transl Med 2021 Oct 9;19(1):419.doi: 10.1186/s12967-021-03092-x.[Pubmed]  Free PMC article

Background: Cystic fibrosis (CF) patients present with a variety of symptoms, including mood and cognition deficits, in addition to classical respiratory, and autonomic issues. This suggests that brain injury, which can be examined with non-invasive magnetic resonance imaging (MRI), is a manifestation of this condition. However, brain tissue integrity in sites that regulate cognitive, autonomic, respiratory, and mood functions in CF patients is unclear. Our aim was to assess regional brain changes using high-resolution T1-weighted images based gray matter (GM) density and T2-relaxometry procedures in CF over control subjects.
Methods: We acquired high-resolution T1-weighted images and proton-density (PD) and T2-weighted images from 5 CF and 15 control subjects using a 3.0-Tesla MRI. High-resolution T1-weighted images were partitioned to GM-tissue type, normalized to a common space, and smoothed. Using PD- and T2-weighted images, whole-brain T2-relaxation maps were calculated, normalized, and smoothed. The smoothed GM-density and T2-relaxation maps were compared voxel-by-voxel between groups using analysis of covariance (covariates, age and sex; SPM12, p < 0.001).
Results: Significantly increased GM-density, indicating tissues injury, emerged in multiple brain regions, including the cerebellum, hippocampus, amygdala, basal forebrain, insula, and frontal and prefrontal cortices. Various brain areas showed significantly reduced T2-relaxation values in CF subjects, indicating predominant acute tissue changes, in the cerebellum, cerebellar tonsil, prefrontal and frontal cortices, insula, and corpus callosum.

Conclusions: Cystic fibrosis subjects show predominant acute tissue changes in areas that control mood, cognition, respiratory, and autonomic functions and suggests that tissue changes may contribute to symptoms resulting from ongoing hypoxia accompanying the condition.

Dr Bhaswati Roy is a Post doc in the Department of Anesthesiology and Perioperative Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA.

Haluk Tekerlek, Bilge Nur Yardımcı-Lokmanoğlu, Deniz Inal-Ince, Uğur Özçelik, Akmer Mutlu^.  Developmental Functioning Outcomes in Infants with Cystic Fibrosis: a 24- to 36-Month Follow-Up Study. Phys Ther  2022 Apr 6;pzac037.doi: 10.1093/ptj/pzac037. Online ahead of print 
[Pubmed]

Haluk Tekerlek

This study aimed to follow the developmental functioning of infants, 3 to 5 months of age, with cystic fibrosis (CF), according to recent published results based on Prechtl General Movement Assessment (GMA).
Methods:Motor repertoire was evaluated using Prechtl GMA, and developmental function was assessed using Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) in infants with CF and their peers who were neurotypical.
Results:Twelve infants with CF clinically stable and 12 infants who were neurotypical, with respective median postterm ages of 14 and 13 weeks, were assessed using GMA. At 24 to 36 months, the Bayley-III was applied to the CF group (median postterm age = 27.5 months) and the control group (median post-term age = 27.0 months). Fidgety movements (FMs) were absent in 5 infants with CF, whereas all infants who were neurotypical had normal FMs. The Motor Optimality Score (MOS) was significantly lower in the CF group (median = 18.5) compared with the control group (median = 26). The CF group had significantly lower composite scores in the Bayley-III cognition, language, and motor domains compared to the control group.
Conclusions:Cognitive, language, and motor development was delayed in infants with CF. Developmental functioning of infants with CF should be assessed as early as possible and monitored, and age-specific early intervention programs should be considered when necessary.

Impact:Children with CF may have motor, cognitive, and language developmental delays compared with peers who are neurotypical during early childhood, and hospitalization was negatively correlated with motor development at 24 to 36 months of age. This study highlights the importance of early assessment of developmental functioning and age-specific, early intervention programs when necessary in infants with CF.

Dr Haluk Tekerlek is in the Faculty of Physical Therapy and Rehabilitation, Hacettepe University, Ankara, Turkey.

Helen K Chadwick, Janice Abbott, Margaret Anne Hurley, Louise Dye, Clare L Lawton, Michael W Mansfield, Daniel Peckham. Cystic fibrosis-related diabetes (CFRD) and cognitive function in adults with cystic fibrosis.  J Cyst Fibros  2022 May;21(3):519-528.doi: 10.1016/j.jcf.2021.04.014. Epub 2021 Jun 14.  Free article [Pubmed]

Helen K Chadwick

Background: Being able to function cognitively is imperative for successful achievement in school, working life, and disease self-management. Diabetes is known to cause changes in brain structure and long-term cognitive dysfunction. This work investigated cystic fibrosis-related diabetes (CFRD) as a mechanism for cognitive impairment in people with CF. It was hypothesised that cognition would be poorer in adults with CFRD than in those with CF without diabetes (CFND) or in healthy controls.

Methods: Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery which provides a comprehensive cognitive assessment with tests mapping onto specific brain regions. Demographic, clinical and self-reported health data were documented for all participants. CF specific clinical variables were recorded for the two CF groups.
Results: Ninety-eight people with CF (49CFRD,49CFND) and 49 healthy controls were recruited. People with CF demonstrated deficits in aspects of verbal and spatial memory, processing speed and cognitive flexibility compared with healthy controls, with all areas of the brain implicated. Those with CFRD had additional difficulties with higher-level processes known collectively as ‘executive function’, which demand greater cognitive load and recruit the prefrontal cortex. Compared with healthy controls, those with CFND and CFRD had an estimated 20% and up to 40% reduction in processing speed respectively.

Conclusion: Managing CF requires higher order executive function. Impairments may be sufficient to interfere with self-care and the ability to perform everyday tasks efficiently. At which point in the CF disease trajectory these difficulties begin, and what may attenuate them, has yet to be determined.

Helen K Chadwick is in the School of Psychology, University of Leeds, Leeds LS2 9JT, UK; Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds LS2 9JT, UK; Adult Cystic Fibrosis Unit, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK.