Neurofibromatosis

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The neurofibromatoses are autosomal dominant diseases
They are the most common neurocutaneous syndrome, a group which includes tuberous sclerosis, von Hippel-Lindau disease and basal nevus syndrome

They are characterised by a tendency to form tumours of both ectodermal and mesodermal tissue
These neurofibromas may occur in the neuraxis, oropharynx/larynx as well as a host of other body systems, with consequential impacts on anaesthetic conduct
Neurofibromatosis is divided based on clinical and genetic features into two major subtypes

A.k.a von Recklinghausen's neurofibromatosis
A.k.a peripheral neurofibromatosis

Genetics

Incidence 1 in 2,500 - 3,300 births
Prevalence 1 in 5,000
Autosomal dominant with ∽100% penetrance but variable expressivity
Up to 50% of cases are 'sporadic' i.e. with no family history
Chromosomal location of the NF1 gene is 17q 11.2

Encodes the protein neurofibromin which has a tumour suppressive role
Mutations in the gene diminish neurofibromin levels and thus tumour development ensues

Diagnostic criteria

Two or more from:

≥6 café-au-lait spots >1.5cm in size (or >0.5cm if pre-pubertal)

By adulthood 95% of those with NF1 will have café-au-lait spots

≥2 neurofibromas of any type, or ≥ plexiform neurofibromas
Axillary or groin freckling (70%)
Optic glioma
≥2 Lisch nodules (benign iris hamartomas)
Distinctive bony lesions e.g. sphenoid bone dysplasia or long bone cortex dysplasia
A first degree relative with NF1

Types of neurofibroma

Cutaneous neurofibromas (>95% of patients) i.e. dermal tumours

Nodular neurofibromas

Arise in peripheral nerves at any site
May be large but do not infiltrate the surrounding tissue
May be paraspinal and grow to an enormous size

Plexiform neurofibromas (30%)

Affect long portions of the involved nerve, infiltrating the nerve and surrounding tissue
Can cause mechanical complications
Can undergo malignant change in 2 - 16% of patients and is a major source of morbidity and mortality in NF1

Pilocytic astrocytomas (15%)

Benign astrocytomas which can arise in the optic nerve/chiasm; optic gliomas
Only 2 - 5% are symptomatic

Others:

Melanotic hamartomas of the iris (95%) i.e. Lisch nodules
Phaeochromocytoma is more common than in the general population (up to 6% of those with NF)
Bony lesions
Intestinal tumours, particularly duodenum and ampulla of Vater
Juvenile chronic myeloid leukaemia
Malignant gliomas (2%)

Other features

Short stature
Macrocephaly
Pituitary abnormalities e.g. GH deficiency
Learning disabilities (50%)
Headaches
Epilepsy
Sylvian aqueduct stenosis and hydrocephalus
Deafness due to conductive hearing loss and delayed central auditory evoked potential conduction times

A.k.a bilateral acoustic neurofibromatosis
A.k.a. central neurofibromatosis

Genetics

Incidence 1 in 33,000 - 40,000
Prevalence 1 in 210,000
Autosomal dominant inheritance but as with NF1 up to 50% are sporadic cases
Chromosomal location of the NF2 gene is 22q 12.1

Encodes the protein schwannomin (merlin) which has a tumour suppressive role
Mutations in the gene diminish protein levels and thus tumour development ensues

Diagnostic features

Bilateral vestibular schwannomas arising from the vestibular branch of CN VIII is the defining feature

Causes gradual, progressive, asymmetrical hearing loss with mean age of onset at 24yrs old

Family history of NF2 plus

Unilateral vestibular schwannoma (<30yrs), or
Two of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract

Segmental neurofibromatosis

Both NF1 and NF2 can present as a non-generalised form where only one body part is affected
It is a form of somatic mosaicism where only some cells possess the gene mutation

Airway

Suspicion of airway tumour if dysphagia, dysarthria, stridor or dysphonia
Difficult airway should be anticipated owing to the presence of neurofibromas of the larynx, pharynx or tongue

Laryngeal tumours typically of the aryepiglottic folds or arytenoids

Cervical region tumours inc. parapharyngeal space can distort the airway
Macrocephaly, macroglossia and mandibular abnormalities add to airway difficulty

Respiratory

Restrictive lung disease from kyphoscoliosis (10 - 25%)
Associated bilateral upper lobe pulmonary fibrosis (up to 10 - 20%) ± pulmonary hypertension and cor pulmonale
Lung parenchymal tumours (rare)
Mediastinal neurofibroma can cause SVCO, tracheal or bronchial compression
Cystic lung disease

Cardiovascular

Hypertension is the most common cardiovascular manifestation (6%)

Often essential hypertension although 30% are secondary due to either renal artery stenosis, aortic coarctation or phaeochromocytoma

Idiopathic hypertrophic cardiomyopathy can occur, which may be due to anormal catecholamine mechanism or outflow obstruction by neurofibromas
Dysrhythmias are more common
Optimise anti-hypertensives if phaeochromocytoma if present

Neurological

May need investigation and optimisation of ICP as 5 - 10% have intracranial tumours ± hydrocephalus
Optimisation of anti-epileptics
Cognitive deficits and learning difficulties require careful planning and may make interventions difficult
Peripheral neuropathy
Stroke due to progressive narrowing of internal carotid arteries
Historical reports of variable response to NMBA are based on poor-quality evidence and are unlikely to be correct
Neuraxial anaesthetic may be contra-indicated due to:

Raised ICP
Presence of spinal neuromas

Gastrointestinal

Can have pain, GI haemorrhage or obstruction from GI tumours
Carcinoid tumours can occur

No apparent intrinsic effect on fertility but higher rates of spontaneous abortion and stillbirth

Pre-term labour (30%) and IUGR are more common
Pelvic or abdominal neurofibromas can necessitate LSCS due to obstructed labour
Pregnancy associated (sometimes rapid) increase in size of tumours with consequent clinical effects
Pregnancy may induce renal artery stenosis, which may be associated with HELPP syndrome

For LSCS, risk - benefit balance needs to be struck between RA and GA

GA may be risky due to difficult airway and hypertension
RA is relatively contra-indicated unless spinal cord lesions have been excluded by imaging
Epidural block may be patchy