Neurofibromatosis 1 Neurofibromatosis 1 associated pain associated pain

syndromessyndromesThomas J Geller, MDThomas J Geller, MD

NF clinic director, CGCHNF clinic director, CGCHAssoc Prof Neurology, SLUAssoc Prof Neurology, SLU

Frequency of Pain as a Frequency of Pain as a complaint in Neurofibromatosis complaint in Neurofibromatosis patientspatients• Though numerous neurologic Though numerous neurologic

complications of NF-1 appear (optic complications of NF-1 appear (optic gliomas, subcutaneous neurofibromas, gliomas, subcutaneous neurofibromas, macrocephaly, plexiform neurofibromas, macrocephaly, plexiform neurofibromas, seizures, LD’s), the most common seizures, LD’s), the most common symptoms causing disability for adult symptoms causing disability for adult patients are pain symptoms. (11.3 % in patients are pain symptoms. (11.3 % in Zeller’s 1 year study of 158 adults)Zeller’s 1 year study of 158 adults)

Headache studies in NF-1Headache studies in NF-1• North reports an incidence of 9% of severe North reports an incidence of 9% of severe

headache. headache. • Zeller found adult incidence of disabling Zeller found adult incidence of disabling

headache to be 18%, but did not break out headache to be 18%, but did not break out the patients with common migraine.the patients with common migraine.

• Recurring headache in DiMaurio’s study Recurring headache in DiMaurio’s study occurred in 46% of NF patients; 14% met occurred in 46% of NF patients; 14% met criteria for migraine, 18% tension headache.criteria for migraine, 18% tension headache.

• Other studies show that migraine incidence Other studies show that migraine incidence in the general population is about 18%, in the general population is about 18%, regardless of severity.regardless of severity.

Age and Pain in NF-1Age and Pain in NF-1

Quality of life with painful Quality of life with painful complications of NF-1complications of NF-1• French dermatology study of mixed adult/ French dermatology study of mixed adult/

ped NF-1 demonstrated that for all aspects ped NF-1 demonstrated that for all aspects of the general questionnaire, including of the general questionnaire, including bodily pain, pts with NF-1 reported lower bodily pain, pts with NF-1 reported lower QOL scores than the general population. QOL scores than the general population.

• Increased severity of the disease was Increased severity of the disease was assoc with increased negative effect on assoc with increased negative effect on bodily pain.bodily pain.

Pediatric NF Pain studyPediatric NF Pain study• Oostenbrink studied 34 NF Dutch Oostenbrink studied 34 NF Dutch

children from 1 to 6 yrs of age using children from 1 to 6 yrs of age using the infant/toddler QOL index.the infant/toddler QOL index.

• Added 7 questions on pain and Added 7 questions on pain and limitations of activitylimitations of activity

• A significant difference in QOL was A significant difference in QOL was identified from kids with bodily pain identified from kids with bodily pain vs those without bodily pain.vs those without bodily pain.

Non-headache pain: (bodily Non-headache pain: (bodily pain)pain)• In the 18 adults with chronic pain, In the 18 adults with chronic pain,

symptoms began in childhood in 7.symptoms began in childhood in 7.• Pain was felt to be clearly organic in Pain was felt to be clearly organic in

83%.83%.• In 17% the cause was unknown.In 17% the cause was unknown.

Causes of peripheral painCauses of peripheral pain• Peripheral nerve or root- 39%Peripheral nerve or root- 39%• Surgical pain- 22%Surgical pain- 22%• Malignant peripheral nerve sheath Malignant peripheral nerve sheath

tumor-17%tumor-17%• plexiform neurofibroma- 11%plexiform neurofibroma- 11%• Subcutaneous neurofibroma-11%Subcutaneous neurofibroma-11%

Outcome of peripheral pain in Outcome of peripheral pain in NF-1NF-1• 77% were able to achieve at least partial 77% were able to achieve at least partial

remission of pain.remission of pain.• Pain was intermittent in ½ of patients.Pain was intermittent in ½ of patients.• Chronic pain was complicated by Chronic pain was complicated by

“breakthru” with movement or contact of “breakthru” with movement or contact of the affected nerve region in most patients.the affected nerve region in most patients.

• Optimal pain management was considered Optimal pain management was considered to be analgesics, antidepressants and/or to be analgesics, antidepressants and/or anticonvulsants. Some required neuro-anticonvulsants. Some required neuro-stimulation or spinal procedures.stimulation or spinal procedures.

Theoretical mechanisms of Theoretical mechanisms of pain supersensitivity in NF-1pain supersensitivity in NF-1• Changes in the excitability of dorsal root Changes in the excitability of dorsal root

entering the spinal cordentering the spinal cord• Study of sensory cultured neurons Study of sensory cultured neurons

reveals enhanced excitability of reveals enhanced excitability of neurons, and increased release of pain neurons, and increased release of pain neurotransmitters CGRP and substance neurotransmitters CGRP and substance P.P.

• Anxiety in the subject over the risk of Anxiety in the subject over the risk of pain being associated with a malignancypain being associated with a malignancy

NeuropathicNeuropathic

May be caused by several processes–Direct tumor infiltration–Nerve damage / demyelination–Nerve compression–Radiation–Chemotherapy (taxols & vincristine)–Viral–Metabolic

NeuropathicNeuropathic

Spontaneous burningIntermittentRadiatingShootingLight touch (allodynia) SharpStabbingPins & needles

Neuropathic pain Neuropathic pain mechanismsmechanisms

Cornerstones of treatment of Cornerstones of treatment of neuropathic painneuropathic pain• Because neuropathic pain has both Because neuropathic pain has both

peripheral and central mechanisms of peripheral and central mechanisms of development and enhancement, development and enhancement, treatment is probably best when treatment is probably best when multiple methods of attack are applied.multiple methods of attack are applied.

• Treatment should be applied early to Treatment should be applied early to avoid “wind-up” mechanisms of avoid “wind-up” mechanisms of enhanced painenhanced pain

Agents for neuropathic painAgents for neuropathic pain• Analgesics including opioids when neededAnalgesics including opioids when needed• Ketotifen for neurofibromas (esp with itching)Ketotifen for neurofibromas (esp with itching)• Calcium channel blocking anticonvulsants, Calcium channel blocking anticonvulsants,

(Neurontin and Lyrica)(Neurontin and Lyrica)• Norepinephrine and serotonin blockers, Norepinephrine and serotonin blockers,

(tricyclics and Cymbalta)(tricyclics and Cymbalta)• Possibly sodium channel blockersPossibly sodium channel blockers• PHYSIOTHERAPYPHYSIOTHERAPY• Relaxation therapiesRelaxation therapies• Surgical managementSurgical management