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Management of Neuropathy in

Persons with HIV Disease or Cancer

David M. Kietrys, PT, PhD, OCS

Rutgers

kietrydm@shrp.rutgers.edu

Mary Lou Galantino, PT, PhD, MSCE

Stockton University

MaryLou.Galantino@stockton.edu

Roberto Sandoval, PT, PhD

University of the Incarnate Word

rosandov@uiwtx.edu

Elizabeth Hile, PT, PhD, NCS, CLT

University of Oklahoma

Elizabeth-Hile@ouhsc.edu

HIV-related Neuropathy

APTA‐Combined Sections Meeting, Anaheim, CA

Feb 2016

R. Sandoval PT, PhD

Assistant Professor

School of Physical Therapy

University of the Incarnate Word

Objectives

Describe the role of microglia in neuropathic pain

Describe the pathophysiology of neuropathic pain in HIV

Describe the clinical profile of patients susceptible to develop HIV related neuropathy

Present evidence based screening tools to identify neuropathic pain sufferers

Pain

• Definition: “An unpleasant sensory or emotional experience associated with actual or potential tissue damage and described in terms of such damage.”

– International Association for the Study of Pain

http://www.iasp-pain.org/Content/NavigationMenu/GeneralResourceLinks/PainDefinitions/default.htm#Pain

Ascending Pain Pathway

IL: intralaminar nucleus of the thalamus, VP:

ventroposterior nucleus of the thalamus.

http://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides-and/ascending-pain-pathway.html

Perception

Transduction/Conduction

Transmission

Modulation

Nerve injury

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Nerve Length influence

De Souza Faleiros A, Lima Resende LA, Zanini MA et al. L4-5-S1 Human Dermatome: A clinical ,electromyographical and surgical findings. Arq Neuropsiquiatr, 2009; 67 (2-A):265-267Botter A, Oprandi G, Lanfranco F et al. Atlas of muscle motor points for the lower limb: implications for electrical stimulation procedures and electrode positioning. Eur J Appl Physiol, (2011) 111:2461–2471

Role of glial cells in neuropathic pain

Coull, Beggs et al. Nature 438, 1017-1021 (15 December 2005) doi:10.1038/nature04223

Mikan J, Zychowska M, Popiolek K et al. Importance of glial activation in neuropathic pain. Euro J Pharma. 2013; 716,106–119.

Coull, Beggs et al. Nature 438, 1017-1021 (15 December 2005) doi:10.1038/nature04223

Mikan J, Zychowska M, Popiolek K et al. Importance of glial activation in neuropathic pain. Euro J Pharma. 2013; 716,106–119.

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Neuropathy in HIVGp-120 binding-HIV lifecycle

Pathophysiology

• HIV Gp‐120 binds with co‐receptors to enter the host cell o [CD4 + (CXCR4 or CCR5)]

• Dorsal root ganglia (CCR5 co‐receptor only) HIV Gp‐120 exposure mediates chemokine production Mitochondria is damage by chemokine exposure HIV infiltrated macrophages produce cytokines that damage 

mitochondria Leads to neuron cell death

• Peripheral Axons (CXCR4/CCR5 co‐receptors) HIV Gp‐120 exposure mediates chemokine production, 

mitochondrial damage and neurite retraction.

Kamerman PR, Moss PJ, Weber J, Wallace VC, Rice AS, Huang W. Pathogenesis of HIV-associated sensory neuropathy: evidence from in vivo and in vitro experimental models. J Peripher Nerv Syst. Mar 2012;17(1):19-31.

PATHOPHYSIOLOGY

Kamerman PR, Moss PJ, Weber J, Wallace VC, Rice AS, Huang W. Pathogenesis of HIV-associated sensory neuropathy: evidence from in vivo and in vitro experimental models. J Peripher Nerv Syst. Mar 2012;17(1):19-31.

Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch, P. Anand, K. Bley British Journal of Anaesthesia 107 (4): 490–502 (2011) Advance Access publication 17 August 2011 . doi:10.1093/bja/aer260

PATHOPHYSIOLOGY

Kamerman PR, Moss PJ, Weber J, Wallace VC, Rice AS, Huang W. Pathogenesis of HIV-associated sensory neuropathy: evidence from in vivo and in vitro experimental models. J Peripher Nerv Syst. Mar 2012;17(1):19-31.

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Clinical ProfileDistal Symmetrical Peripheral Neuropathy (DSPN) 30‐60% of all people living with HIV and AIDS (PLWHA) 

Bilateral involvement at the extremities

Clinical presentation: Decreased DTR at the ankle

Decreased sensation

No significant strength loss

No significant range of motion deficits

Paresthesias

Painful night crampsDworkin, R. H., et al. 2003. Arch Neurol, 60(11), 1524-1534.Martin, C., Pehrsson, P., Osterberg, A., Sonnerborg, A., & Hansson, P. (1999). Crna, 10(3)101-106Moore, R. D. et al. (2000). Aids, 14(3), 273-278.Wulff et al. HIV: Advances in research and therapy, Dec 1998. http://www.iapac.org/clinmgt/cns/wulff_hart83.html. Accessed, Nov. 1999

Clinical Profile Symptomatic DSPNPLWHA with

• Hx of DM

• Older (increased risk each decade of life)

• CD4 <200 cell/mm3

• On NRTI based regimen

• On statins

• High baseline VL

• Tall (increased risk each 5cm)

• Recently began ART

HIPAA

HIPAA

Evans SR, Ellis RJ, Chen H, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. 2011;25(7):919-928.

Screening tools

Screening measuresDN4 Questionnaire

V. Spallone, R. Morganti, C. D’Amato, C. Greco, L. Cacciotti, G. A. Marfia.Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy. Diabetic Med; 2012, 29(5), 578-585.

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DN4

At the cut‐off score of 4/10o sensitivity of 80%, 

o specificity of 92%

oROC 0.94 

opositive predictive value (PPV) of 82% 

onegative predictive value (NPV) of 91% and 

o LR(+) 9.6, LR(‐) .21

At the cut‐off of 3/10o LR(+) of 5.3.

S-LANSS

• 80% accuracy to identify neuropathic pain of different etiology

o Sensitivity 78%

o Specificity  68%

o LR + 2.45, ‐LR 0.55

Bennett MI, Smith BH, Torrance N, Potter J. The S‐LANSS Score for Identifying Pain of Predominantly Neuropathic Origin: Validation for Use in Clinical and Postal Research. Pain, Vol 6(3):149‐158, 2005

Clinical bottom line

• Suppress HIV replication as primary intervention

• Additional studies are needed to identify effective analgesic interventions

o focusing on glial cell inhibition and/or anti‐inflammatory properties

• Quick and effective screening tools are available and may serve in identifying patients with clinical signs of neuropathic pain.

Objectives

Describe the role of microglia in neuropathic pain

Describe the pathophysiology of neuropathic pain in HIV

Describe the clinical profile of patients susceptible to develop HIV related neuropathy

Present evidence based screening tools to identify neuropathic pain sufferers

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Chemotherapy‐Induced Peripheral Neuropathy

Elizabeth Hile PT, PhD, NCS, CLTDirector of OUHSC/SCC Cancer Rehab Science Program

Assistant Professor, OUHSCOklahoma City, OK

Prevalence of CIPN

• Common

– 68.1% (95% CI =57.7‐78.4%) within 1st month of last chemo dose

– 64% of 104 colorectal survivors 

– Up to 100% for some regimens

Seretny 2014, Pettersson 2014

Impact of CIPN

• Worse QoL and Independence

– Sleeping, driving, standing, walking, stairs, balance, exercise, socializing

• Dose‐limiting = Lower Survival?

Bhatnagar 2014, Speck 2012

CIPN Transcends Cancer Type• The treatment received is more predictive than the cancer site

Others: Targeted therapies, Thalidomide

Drug Class Common Drugs Cancers Treated

Taxanes Docetaxel (Taxotere®)Paclitaxel (Taxol®, Abraxane®)

Breast, ovarian, lung

Platinums Cisplatin, CarboplatinOxaliplatin

Breast, ovarian, lung, testicular, bladder, colorectal, GI, H&N

Epothilones Ixabepilone (Ixempra®) Breast

Vinca alkaloid Vinorelbine (Navelbine®)Vinblastine, Vincristine

Breast, testicular, lymphomas, leukemias, sarcomas

Proteasome Inhibitors

Bortezomib (Velcade®) Multiple Myeloma

Pathophysiology of CIPN

• Peripheral = outside blood‐brain barrier

• Threshold dose, cumulative

– May be delayed, but generally signs by 2 wks

– Coasting

• Rx = Dose delay, reduction, cessation

CIPN: Importance of Dose

• Synergistic  Effects (ACT = Adriamycin, Cytoxan,  Taxol)

Drug Class Common Drugs Incidence Dose

Taxanes Docetaxel (Taxotere®)Paclitaxel (Taxol®, Abraxane®)

‘Strong assoc.’‘Strong assoc.’33% Grade 3/4

371 mg/m2

1000 mg/m2

250 mg/m2

Platinums Cisplatin, CarboplatinOxaliplatin

Strong65‐98%; 100%

>300,>400mg/m2

Epothilones Ixabepilone (Ixempra®) 30% Grade 3/4

Vinca alkaloid Vinorelbine (Navelbine®)Vincristine Early signs >4 mg/m2

Argyriou 2008 (2), Lee 2006, Quasthoff 2002

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Pathophysiology: Targets of CIPN

• Ganglion (DRG)

– Apoptosis

• Axon

– Longest axons appear most vulnerable 

• Myelin

– Nodes of Ranvier

SymptomatologyClinical Presentation of CIPN

• Sensory– Numbness/ tingling

– May or may not be PAINFUL (Wolf 2012)

– Allodynia

• Motor

– Weakness, esp distally

– Cramping

• Autonomic

– Digestion, breathing, regulation of blood pressure &                     body temp, sexual function

Diagnosis

Use of Noninvasive, Clinically Feasible 

Tools to Diagnose CIPN

CIPN: NCI CTCAE v3 GradingAdverseEvent

Grade  1 Grade 2 Grade 3 Grade 4 Grade 5

Motor Neuropathy

Asymptomatic, weakness onexam

Symptomatic weakness interfering with function but not ADL

Weakness interfering with ADL,bracing or assist to walk

Life‐threatening, disabling (paralysis)

Death

Sensory Neuropathy

Asymptomatic, loss of DTR or paresthesia

Sensoryalteration interfering with function but not ADL

Sensory alteration interfering with ADL

Disabling Death

NCI CTCAE v3 appears to underestimate prevalence and severity,  a problem not adequately fixed by version 4. (Cavaletti 2010, Argyriou 2014)

Screening for Sensory CIPN

• Self‐report

– Neuropathy vs Arthralgia:  Numbness/ tingling

– Functional = Dropping, off‐balance

• Performance

– DTR

– Vibration

– Touch may be altered with some agents (vinca) but is generally not recommended

Screening for Motor CIPN

• Self‐report

– Neuropathy vs Myopathy = Tripping, scuffing, fine motor

• Performance

– Isolated, distal strength testing

• Manual Muscle Testing

CAUTION: Functionally significant strength deficits may become evident only with fatigue!

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Screening for Autonomic CIPN

• Self‐report

– Lightheaded

– Other?

• Performance

– Orthostatic BP

– Other?

Summary: CIPN Screening

• Sensory Loss

– Interview: FACT/GOG‐Ntx, VAS, BPI

– Exam

• Weakness

– Interview 

– Exam

• Autonomic

Don’t Assume. . . ASK and TEST!!

• Full Extent of Balance Deficits May NOT be Obvious

– With ‘mild’ CIPN 

• Postural control compared to severe DPN (Wampler 2007)

• Neuropathic symptoms were common & troublesome (Kautio 2011)

• Survivors rarely recognize their own toe weakness

Prognosis of CIPN

• Meta‐analysis

– 60.0% (36.4–81.6) prevalence at 3 months 

– 30.0% (6.4–53.5) at > 6 months

• 35% of adult ALL survivors have impaired foot/ankle function

• Deficits can persist > 2 yearsSeretny 2014, Hile 2010

Outcome Measures & Evidence for Effectiveness of PT Interventions

in Patients with Chemotherapy Induced Peripheral Neuropathy (CIPN) or

HIV-related Neuropathy

Mary Lou Galantino, PT, PhD, MSCEProfessor, Stockton University

MaryLou.Galantino@stockton.edu

David M. Kietrys, PT, PhD, OCSAssociate Professor, Rutgers University

kietrydm@shrp.rutgers.edu

Impairments and functional limitations due to neuropathy are seen clinically and have been reported in the literature

In patients with chemotherapy-induced peripheral neuropathy (CIPN)

• Mols et al., 2014; Speck, 2012

• Worse QOL and independence

• Kneis et al. (2015)

• Balance impairments

In patients with HIV-related neuropathy

• Galantino, Kietrys, et al. (2014)

• Lower self-reported LE function

• Lower physical health related quality of life

• Sandoval et al. (2014)

• Moderate to severe pain, sleep disturbances, and limited ambulation distances

In patients with HIV disease

• Richert et al., 2014

• poorer 5STS time and 6MWD in HIV+ persons vs. healthy adults.

• test performance deteriorated over 2 years in HIV+ persons.

In patients with peripheral neuropathy

• Manor et al. (2009)

• Reduced gait performance

• Impaired standing balance

• Manor et al. (2008)

• increased walking variability and local instability

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Bottom LinesSelf-reported LE function, using either the LEFS or the LLFI, was significantly lower in HIV+ patients with DSP than in those without DSP. Scores reflect ≤50% of normal/full function in those with DSP.

Mean LLFI score 32.8 points lower in those with DSP

Mean LEFS score (raw) 21.2 points lower in those with DSP

Bottom LinePhysical Summary Score component of quality of life (MOS-HIV) significantly lower in HIV+ participants with DSP than those without.

Mean Physical Summary Score 15.2 points lower in those with DSP

Outcomes for Patients with Peripheral Neuropathy

Neuropathy Severity

Symptom Ratings

Sleep Quality

QOL

Physical Performance

and Sensory Tests

Function

Disability

Things to consider when measuring outcomes:

• Neuropathy-specific tools vs. generic tools that can be applied to patients with neuropathy

• Self-report vs. direct (objective) measurement vs. tools that contain both

• Psychometric properties / measurement properties• Validity• Reliability• Responsiveness to Change

• Minimal Detectable Change scores (MDC)• Minimally Important Clinical Difference (MCID)

• Purpose• Clinical

• Establish baseline• Monitor response to care• Tracking of clinical outcomes

• Research• Epidemiological studies• Intervention studies

• Practicality• Time, cost, permissions/fees• Consistent use amongst clinicians in a given clinic or system

Outcome Tools for Peripheral Neuropathy

Tests used to screen for presence of neuropathy

Brief Peripheral Neuropathy Screen (Ellis et al., 2005)• 1 or more subjective symptoms + diminished ankle jerk and/or vibration sensation in great toe • sensitivity of 49%; specificity of 88%

Total Neuropathy Score (Cornblath et al., 1999)• Score derived from results of:

• Subjective grading of symptoms• Nerve conduction velocity• Quantitative sensory tests

• Originally developed for CIPN. Has been used in diabetic neuropathy and HIV-related neuropathy.

• Validity and reliability good. Has been used as an outcome in clinical trials, but not practical as a clinical outcome measure due to need for NCV.

Michigan Neuropathy Screening Instrument (MNSI) (Feldman et al., 1999)• 15 item questionnaire with yes/no responses to indicate severity and frequency of neuropathic

symptoms. • As a diagnostic screen, sensitivity and specificity depending on cut-off score. For cut-off score of

1.5, 79% sensitivity. For cut-off score of 3, 94% specificity (Moghtaderi et al., 2006)• Has been used as a pain outcome tool (Kluding et al., 2012)

Subjective Peripheral Neuropathy Screen See next slide!

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Subjective Peripheral Neuropathy Screen (SPNS) (McArthur, 1998)

• 6 sections; all self-report• Quick and inexpensive• Validated in HIV+ patients• Sensitivity 51%; specificity 84%• Developed as a screening tool,

but may have utility as an outcomemeasure (further study is needed to determine utility of SPNS as an outcome tool).

Currently being used by Kietrys et al. in the study: “Self-Reported Disability in HIV+ Persons with and without HIV-related Distal Sensory Polyneuropathy”

Brief Pain Inventory Permission required. http://www3.mdanderson.org/depts/symptomresearch/

Widely used in study of cancer, HIV disease and neuropathic pain. (Cleeland et al., 1994; Keller et al., 2004)

Mean severity score (items 3-6) Mean Interference score (items 9A-9G)

Neuropathy Pain Scale (Galer & Jensen, 1997)

• Predictive and discriminative validity (score of >43 suggestive of neuropathy)

• Sensitive to change due to effect of treatments

• Can be scored 4 ways:

• NPS-10: 0-100 point composite / global score; all items

• NPS-8: only those items re: neuropathy pain

• NPS-NA (non-allodynia): excludes “surface pain” and “skin sensitivity”

• NPS-4: includes “sharp pain”, “hot pain”, “dull pain” and “deep pain”

Pittsburgh Sleep Quality Index (Buysse et al. 1989)

2 page, 10 item questionnaire covering 7 components of sleep, each with a subscale score of 0-3

• Subjective sleep quality• Sleep latency• Sleep duration• Habitual sleep efficiency• Sleep disturbances• Use of sleeping medication• Daytime dysfunctions

• Composite score is sum of all 7 component scores

• “good sleeper” score <5 out of 21• “poor sleeper” score of 5 or more out of 21• 89.6% sensitivity and 86.5% specificity for identifying good and poor

sleepers

HIV related neuropathy

Outcome Measures to Assess Impact of HIV disease and/or HIV-related Neuropathy

• Pain • Brief Pain Inventory (Cleeland & Ryan, 1994)• Visual Analogue Scales; Numerical Pain Scales; Wong-Baker Faces • Neuropathy Pain Scale (Galer & Jensen, 1997)• SPNS (screening tool; applicable as an outcome tool?)

• Affective state (depression)• Beck Depression Inventory II (not specific to HIV or neuropathy)

• Physical Performance / Function / Gait / Balance• Self-Report: LEFS; LLFI (used in HIV sample by Galantino et al., 2014)• Direct Measurement examples: 6 minute walk test; 5 time sit-to-stand test; others• Balance: many tools available but validation in HIV population not reported

(Examples: Single leg stance time; Multidirectional reach test)

• Sensory testing: Semmes Weinstein monofilaments; Tuning fork; Biothesiometry

• Quality of Life: MOS-HIV (developed from SF-36 for patients with HIV disease)

• Sleep: Pittsburgh Sleep Quality Index (Buysse et al. 1989)

• Self-reported disability• WHO-DAS (generic self-report disability tool)• HIV Disability Questionnaire (HDQ) (O’Brien et al. 2013; 2014)

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Tests used to screen for presence of neuropathy associated with HIV disease (Galantino et al., 2013)

Neuropathy Severity Score (Cettomai et al., 2010)• 3 parts (a) Presence and severity of symptoms (b) functional limitations (c)

ankle reflexes• sensitivity 67%; specificity 92% in HIV+ patients in Kenya

Single Question Neuropathy Screen (Kandiah et al., 2010)• “Do you experience tingling, burning, or numbness in your feet or hands?”• Sensitivity 96%; specificity 80% in HIV+ patients in Zambia

Quality of Life Tool: FAHI

Functional Assessment of Chronic Illness Therapywww.FACIT.org(need to register on FACIT web site in order to download scoring instructions and related documents)

Functional Assessment of Human Immunodeficiency Virus Infection (FAHI)

• 4 page self-report tool; 5 domains of QOL:• Physical well-being• Emotional well-being / living with HIV• Functional and global well-being• Social well-being• Cognitive functioning

• Psychometrically sound (valid and sensitive to change) (Peterman et al., 1997)

Quality of Life Tool: MOS-HIV

Adapted from SF-36 for use in patients with HIV diseasehttp://www.proqolid.org/instruments/medical_outcome_study_hiv_health_survey_mos_hiv

MOS-HIV• 7 page self-report (1st page completed by clinician) • Easy and fast to administer, but scoring is cumbersome (can be expedited by creating

a syntax on SPSS). • Intended for research applications more so than clinical use. • Generates Mental Health Summary and Physical Health Summary scores.

Self-reported Disability

In development: The HIV Disability Questionnaire (HDQ) O’Brien et al. (2013; 2014)

70 item tool the generates reflects both the severity and episodic nature of impairments associated with HIV disease.

Internal consistency reliability and construct validity has been reported (in Canadian and Irish cohorts) and good test-retest reliability has been reported (Canadian cohort).

Further validation outside of Canada is currently underway.

CIPN

Outcome Measure

• Use of Semmes-Weinstein monofilaments (SWM) and Chemotherapy-Induced Neurotoxicity Questionnaire (CINQ) in the detection of CIPN

• Statistically significant difference between control group and group treated with oxaliplatin, paclitaxel, or docetaxel, for all symptoms assessed in the CINQ

• Lower limbs more severely affected

• Patients had increased frequency and severity of changes in all points assessed with SWM compared with controls

• CINQ and SWM may be valid tools for diagnosing SIPN in oncology practice

Da Silva et al., 2014

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Outcome Measures to Assess Impact of CIPN

• Most widely used scales to assess CIPN:• Common Toxicity Criteria (CTC) scales• World Health Organization (WHO) scale• Eastern Cooperative Oncology Group (ECOG) scale• National Cancer Institute- Common Toxicity Criteria (NCI-CTC)• Ajani Scale

• Comparisons found among scales:• Neither NCI-CTC nor the WHO scale demonstrated clear superiority in reliability • NCI-CTC criteria appeared to result in greater frequency of grade 3 CIPN

compared to the WHO, ECOG, and Ajani scales• Conclusion: CTC scales are quick to use, easy to administer, but inter-observer

disagreement is frequent

Cavaletti et al., 2010

• Functional assessments:• Functional Assessment of Cancer Therapy/Gynaecologic Oncology

Group neurotoxicity (FACT/GOG-Ntx)

• Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane)

• Peripheral neuropathy scale (PNS)

• Oxaliplatin-associated neuropathy questionnaires

• Scale for Chemotherapy-Induced Long Term Neurotoxicity (SCIN)

• Patient Neurotoxicity Questionnaire (PNQ)

• Comparisons:• PNQ showed greater impact on CIPN on daily activities than NCI-CTC

• SCIN and FACT/GOG-Ntx both showed good psychometric qualities

• Overall Conclusion: • From available literature, existing scales currently being used are not

satisfactory for evaluation CIPN

Cavaletti et al., 2010

Outcome Measure QLQ-CIPN20

• Clinimetric analysis conducted to evaluate reliability, validity, and responsiveness to change over time

• Results:• Alpha coefficients for sensory, motor, and autonomic scales were 0.88,

0.88, and 0.78 respectively

• Moderate correlations were found QLQ –CIPN20 and Brief Pain Inventory pain severity items

• Sensory and motor scales exhibited moderate-high responsiveness to change

• Factor analysis indicated the the 16-item version formed distinct factors for lower and upper extremity CIPN

Smith et al., 2013

Outcome Measure to Assess Disability

• Goal: Develop interval-weighted scale to capture activity limitations and participation restrictions in patients with CIPN using the Rasch methodology and determine its reliability and validity

• Rasch analyses determined whether model expectations would be met and if adaptations were made to obtain proper model fit for internal validity

• External validity obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale

• The final CIPN-R-ODS consisting of 28 items fulfilled all model’s expectations with proper validity and reliability

• Conclusion: Final CIPN- R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients

Binda et al., 2013

Outcome Measures to Assess Impact of CIPN in Pediatrics

• Pediatric Modified-total Neuropathy Scale (ped-mTNS)

(Gilchrist &Tanner, 2012; Gilchrist et al. 2014)

• Reliable and valid in school-age children with relevant functional limitations

Oncology Section Task Force on Breast Cancer Outcomes: Clinical Measures of Chemotherapy-induced Peripheral Neuropathy – A Systematic ReviewHile E, Levangie P, Ryans K Gilchrist L (2015)

• EDGE Task Force identified all published measures of CIPN meeting the criteria of: clinically feasible, addressing the CIPN experience, and with published psychometric properties established in survivors of breast cancer

• Identified measures were systematically reviewed and scored according to the Breast Cancer EDGE Task Force Rating Scale from 1 (Do Not Recommend) to 4 (Highly Recommend)

• Of 11 measures meeting the review criteria, only one, the Functional Assessment of Cancer Therapy/ Gynecologic Oncology Group-Neurotoxicity Scale (FACT/GOG-Ntx) received the highest rating of 4

• FACT-GOG-Ntx has high clinical utility for PT during screening or assessment of CIPN in breast cancer survivors who have received neurotoxic chemotherapy, however it is not recommended for use in isolation

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Case Report: Persistence of CIPN

• 81 year old female received paclitaxel after mastectomy

• Prior to treatment patient was socially active with 1.2 m/s gait speed, no reported functional deficits, and performance at ceiling on balance and gait portions of Short Physical Performance Battery (SPPB)

• SPPB given at baseline, 12 weeks, and 2.5 years

• Results at 12 weeks and 2.5 years:• Decrease in balance and gait measures as large as 50%

• Self reported recurrent falls, cane use, and mobility related disability

• Rapid onset and long term persistence of mobility disability

Hile et al., 2010

Short Physical Performance Battery

http://www.citrage.com/professional-space/sarcopenia/sarcopenia-diagnosis?lang=en

Outcome Measures: Our SuggestionsFor patients with CIPN

To assess impact of CIPN and its sensory and motor impairments, use the appropriate FACIT tool such as FACT/GOG-Ntx or the European Organization for Research and Treatment of Cancer questionnaire (EORTC CIPN20)

Plus, further measures to capture sensory, motor and autonomic deficits specific to each survivor, such as:

BPI (permission required), or NPS for pain

CIPN-R-ODS for disability

Specific to Breast Cancer survivors, see Hile, et al. (2015): Oncology Section Task Force on Breast Cancer Outcomes: Clinical Measures of Chemotherapy-induced Peripheral Neuropathy: A Systematic Reviewhttp://www.readperiodicals.com/201507/3900361821.html

For patients with HIV-related neuropathy

Pain: VAS or Neuropathic Pain Scale (NPS) or Brief Pain Inventory (BPI) (permission required for BPI)

Symptom Severity: Subjective Peripheral Neuropathy Screen (SPNS)

Lower Extremity Function (self-report): LEFS or LLFI

Physical Performance / Sensation•6 minute walk test•5 time sit to stand test•Multi-directional reach test or one-leg stance time

•Semmes-Weinstein monofilament

QOL: FAHI (FACIT.org)

Disability: WHO-DAS

If you had to narrow it down to 3 tools…

BPI or NPS + LEFS or LLFI + FAHI or WHO-DAS

Evidence for PT Interventions

ModalitiesManual Therapy

Exercise

Complementary &

Alternative Therapies

Night Splints

Exercise• For patients with HIV disease in general

• O’Brien et al. (2008) Systematic review of resistive exercise

• increases in weight and arm and thigh girth; trends toward improvement in heart rate and exercise time

• individual studies found improved strength and psychological status. 

• O’Brien et al. (2010) Systematic review of aerobic exercise 

• improved fitness, body composition, and well‐being

• For patients with HIV‐related neuropathy

• Gale (2003)

• 2 case studies of bundled PT Tx that included stretching exercises

Exercise

For patients with CIPN

• Wonders et al. (2011)

• Cancer survivors appear to tolerate physical activity program to mitigate pain caused by CIPN

• Wonders (2012)

• Breast cancer survivors who did recommended physical activity reported significantly higher QOL and experienced less pain

• Stubblefield et al., (20120

• Exercise may improve or attenuate symptoms and improved function through local effects on peripheral nerves

• Tofthagen et al. (2012)

• Strength training, balance and functional training improved balance and strength 

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ExerciseFor patients with CIPN

Streckmann et al. (2014)

• RCT with lymphoma patients undergoing treatment

• Exercise including sensorimotor training improved QOL, balance, physical performance level, and mobility. Reduced restrictions form side effects of peripheral neuropathy

Henke et al. (2014)

• Strengthening and endurance training + breathing techniques in lung cancer patients

• Positive impact on independence with ADLs

• Improved endurance and strength

• Single factors influencing QOL can be improved

Phillips et al. (2015)

• Prostate cancer survivors: 3 or more hrs/wk of walking improved hormone functioning and vitality.

• Effect more notable in those who walked at a faster pace

• Weightlifting was associated with slightly increased urinary incontinence

Mols et al. (2015)

• Colorectal cancer survivors: Not meeting the recommended 150 minutes or more (per week) of moderate to vigorous exercise was associated with more CIPN symptoms; meeting the guidelines was associated with less CIPN symptoms and higher health related QOL

ExerciseWhat do we know about exercise for  neuropathy in general?

• Kluding et al. (2012)

• 10 wks of aerobic/strengthening exercises in pts with diabetic

neuropathy. Improved neuropathic symptoms 

and improved cutaneous nerve fiber branching

• Streckmann et al. (2014)

• Systematic review of exercise for patients with peripheral neuropathy

• 10 RCTs and 8 controlled clinical trials; most used patients with diabetic neuropathy

• “exercise is feasible, safe, and promising supportive measure”

• Balance exercise appears to have highest effect  on motor and sensory symptoms

• Endurance training has potential to prevent onset and delay progression of diabetic (metabolically induced) neuropathy

• Kneis et al. (2015)• Suggest beneficial findings re: exercise in patients with diabetic neuropathy can be translated to cancer survivors

• In patients with diabetic neuropathy, exercise appears to stimulate endothelium dependent vasodilation and endoneural blood flow with a  long term positive effect on oxygen delivery and reduction in pain

• Kietrys et al. (2015; in progress)

• Systematic reviews of effects of exercise on balance (2015) and gait (in progress).  

ExerciseAn exercise regimen prevents development of paclitaxel induced peripheral neuropathy in a mouse model

Park et al. (2015)

Pre‐clinical trial

Exercise can partially abrogate signs of axonal degeneration such as• reduced epidermal nerve fiber density

• thermal hypoalgesis

Exercise normalized levels of detyrosinated tubulin (normally elevated after exposure to paclitaxel)

ExerciseKietrys et al. (2015; in progress)

Systematic reviews of effects of movement‐based therapies or exercise on balance (2015) and gait (in progress) in patients with neuropathy.    

Gait SpeedStride Length

TENSfor patients with CIPN

• Pachman et al. (2015)• Pilot study of “Scrambler therapy” (a form 

of TENS)• 10 daily 30 min. sessions• 53% reduction in pain, 44% reduction in 

tingling; 35% reduction in numbness

• Smith et al. (2010)• Pilot study of a patient‐specific cutaneous 

electrostimulation device (MC5‐A Calmare) in 16 patients with CIPN

• 10 days of 1 hour tx sessions• Use of device appeared to dramatically 

reduce pain

for patients with HIV‐related neuropathy 

• Galantino & Mc Reynolds (1995)• Case series using microcurrent• Reduced or absent pain in 97% of 

patients; improved gait in 76% of patients

• Gale (2003)• 2 cases, bundled PT Tx including 

microcurrent(to be summarized on a later slide)

What do we know about TENS for diabetic neuropathy?Jin et al. (2014)  Systematic review and meta‐analysis of 3 RCTs 

• Reductions in mean pain score were significantly greater in TENS group than in placebo TENS group in 4 weeks and 6 weeks follow‐up [4 weeks, ,  but not in 12 weeks follow‐up 

• TENS therapy was associated with significantly subjective improvement in overall neuropathic symptoms in 12 weeks follow‐up [WMD‐0.18, 95% CI (‐0.32, ‐0.051)]

• No TENS‐related adverse events were registered in TENS group• TENS therapy may be an effective and safe strategy in treatment of symptomatic DPN. • Due to small sample and short‐term treatment duration, large multi‐center RCTs are needed to further 

evaluate the long‐term effect of TENS on DPN

Night Splints• CIPN

• No studies to date

• HIV‐related  neuropathy

• Sandoval et al., 2013• RCT: Night splints vs. control (liner only)

Proposed mechanism: Peripheral inhibition of external stimuli.

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Night Splints

• What do we know about other night splints for diabetic neuropathy?• No studies to date.

Clinical Bottom Line• One RCT to date suggests efficacy for pain control in patients with 

HIV‐related DSPN. Further study is needed to validate these findings.

• Consider a trial of night splints on a case by case basis in patients with HIV‐related neuropathy or CIPN.

Manual TherapyFor patients with CIPN

• Cunningham et al. (2011)• Case report:  45 yo female with 

adenocarcinoma• Massage, 3X/wk for 6 weeks,  

effective in reducing CIPN symptoms (tingling, numbness and pain) and improved quality of life

• Mechanisms unclear (changes in blood flow?) 

For patients with HIV‐related  neuropathy

• Gale (2003)

• 2 cases; STM and joint mobs as part of combination therapy

(to be summarized on a later slide)

What do we know about manual therapy for diabetic neuropathy?• Chatchawan et al. (2015)

• RCT:  Thai foot massage (3x/wk for 2 wks) compared to control• Improved balance (TUG and one‐leg stance); improved sensation (Semmes‐Weinstein monofilament); 

improved knee, ankle and 1st MTP ROM

Bundled PT for HIV related neuropathy (Gale, 2003)

2 patients with HIV related neuropathy

STM + joint mobilization + stretching exercise + microcurrent + home program (stretching and towel desensitization)

• Joint mobs: grade III and IV P‐A and A‐P glides of tarsal / metatarsal / phalangeal joints and distraction of proximal phalanx.

• Stretching of any tight musculature in ankle/foot• Micro‐current to multiple LE points, 0.5 Hz X15 min.

Intervention dose:  2‐4 X / month plus home program for 12 or 18 months

• Case 1: decreased pain and numbness; improved stride length and ambulation tolerance

• Case 2: decreased pain; able to return to work despite progressive atrophy of foot intrinsic muscles at around 12 months

CAM therapies

• For patients with CIPN

• Brami et al. (2015)• Systematic review of natural 

products (12 studies) and complementary therapies (1 study)

• One study of electroacupuncture: not superior to placebo

• Franconi et al. (2013)• Systematic review of acupuncture• Only 1 RCT to date

• “acupuncture may be beneficial for CIPN”

For patients with HIV‐related neuropathy  

• Galantino et al. (1999)• Case series using low‐voltage 

electro‐acupuncture for 30 days• Reduced pain in 5 of 7 patients• Improved function in all patients• Improved H‐reflex parameters

• Kietrys et al., 2016• Case series using yoga

For patients with peripheral  neuropathy  

Li & Manor (2010); Manor et al. (2013)• Improved 6MWT, timed up and 

go, stride length, and plantar sensation after 24 week Tai Chi intervention

• Increased complexity of standing center‐of‐pressure dynamics after 24 weeks of Tai Chi

YOGA FOR PERSONS WITH HIV-RELATED NEUROPATHY: A CASE SERIESKietrys DM1, Galantino ML2, Logan K1, Gould-Fogerite S1, O’Brien K3, Cohen ET1, Jermyn R4, Parrott JS1

1Rutgers; 2Stockton University, 3University of Toronto, 4Rowan University

Inclusion Criteria• Age 18-65 years, HIV+ with controlled HIV

disease status• Clinical diagnosis of DSP in the feet• Average foot pain at least 4/10 as measured

by the numerical pain scale• Stable pharmacologic management of pain• Able to ambulate without assistance of

another person for 6 minutes

Yoga Intervention: 4 weeks of twice-weekly 90 minute yoga classes (administered by a trained instructor) and home yoga practice on non-class days

Exclusion Criteria• Current opportunistic infection,

dementia, or diabetes• Open wounds or sores on feet• Serious medical conditions that

would impair ability to participate in testing or yoga

• Regular practice of yoga in past 6 months

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Prospective Surveillance Model Breast Cancer Survivors

• Women’s perspectives about their impairments and functionallimitations secondary to breast cancer treatment

• Reported being uniformed regarding side effects but surprised that they did not always disappear after treatment

• Patients expressed strong needs for education, information, and intervention for these side effects

• Despite evidence that exercise is effective at preventing and managing side effects, few patients actually referred for rehabilitation

• Prospective surveillance model Serve needs of women with breast cancer by providing education and information about side effects, reducing incidence and burden of side effects through treatment, and enhancing access to rehab

Binkley, et al. (2012)Self Management strategies for CIPN

• Self-management strategies utilized by women with CIPN:• Movement

• Attitude awareness

• Logistics to simplify demands

• Environmental change

• Women may be willing to try interventions that focus on exercise, mindfulness, occupational therapy, & environmental planning for the management of CIPN

Speck et al. (2012)

PT Interventions Our Evidence-Based Recommendations

For patients with CIPN

• Exercise (Grade A)

• TENS (Grade C, based on 2 pilot studies)

• Massage (Grade D, based on 1 case study)

Recommended for patients with HIV-N• Night splints (Grade A, based on

a single 1b RCT)

• Exercise (Grade D, based on expert opinion and extrapolation from research on pts with diabetic neuropathy)

• Combined PT (STM, joint mobs, stretching, microcurrent, and desensitization (Grade C, based a single case series)

Recommended , with reservations, for patients with HIV-N

• Yoga (Grade C, based on a single case series with mixed findings)

Acknowledgements

Garden State Infectious Disease Associates, Voorhees, NJ

Dr. Scott Parrott, Rutgers

Dr. Kelly O’Brien,  University of Toronto

Dr. Tracy Davis, Rutgers

Stephanie Szeliga, SPT, Stockton University

Quang Tran, SPT, Rutgers 

Lauren Schott, SPT, Rutgers

Lianne Previti, SPT, Rutgers

Matt Lewis, SPT, Rutgers

Steve Melchoirre, SPT, Rutgers

Stephanie Silva, SPT, Rutgers

Matt Leusner, SPT, Rutgers

Mark Krimmel, SPT, Rutgers

Michelle Heinneman, SPT, Rutgers

Mike Spirito, SPT, Rutgers

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Pilot study: does lower extremity night splinting assist in the management of painful peripheral neuropathy in the HIV/AIDS population? Journal of the International Association of Physicians in AIDS Care: JIAPAC, 9(6), 368-381.

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