GSDM: PAST PRESENT & FUTURE

RM Clemmons, DVM, PhD, CVA, CVFTGainesville, FL

German Shepherd Degenerative Myelopathy

(GSDM) A chronic, progressive

neurodegenerative disease

Initial signs are due to TL spinal cord disease

Represents an autoimmune disorder

Signalment

Breeds German Shepherd dogs Belgium Shepherds Old English Sheepdogs Rhodesian Ridgebacks Weimaraner Probably Great Pyrenes

Age > 5 years old (usually 8-

9)

Sex Equal

Onset 1 month to 1 year

Clinical Course Paralysis within 3

to 6 month without treatment

Signs of GSDM

Histopathology

Axon and myelin loss Swollen axons Patchy demyelination

Astrocyte proliferation

Increase in vasculature

Diagnosis1. Physical and Neurologic Examination

History of chronic progressive posterior paresis in susceptible breed

TL (non-localized) dysfunction

2. Negative Neural Imaging3. Normal Electrodiagnostic Exam

Might have altered spinal evoked response

4. Abnormal CSFLumbar CSF changes

Greta

Signalment

8 yr F/S GSD Weakness Posterior Paresis

S

Greta History

Seemed to be slower over last 6 months Trouble getting up

Vet checked for HD Minimal response to

NSAIDs

Worse over last 30 daysS

Greta

Greta Neurologic Examination

Head- -NAF CN- -NAF Mild Neck Pain (C6) Forelegs- -NAF (slight

dysmetria) Rear Legs-

Slight hyperflexia L>R CP deficits Bilaterally Babinski L Hypermetria

Mild Back Pain (TL)

O

Greta Localization of

Lesion D A M N N I I I T T VO

T3-L3 Spinal Cord

IVDD, GSDM

MyelitisGME

Spinal Tumor

Greta Differential Dx

?

Diagnostic Approach ?

Treatment ?

P

• Problem List1. Posterior Paresis

2. Foreleg Hypermetria

3. Neck & Back Pain

1. GSDM2. IVDD3. Infect/Inflamm4. Neoplasia

Greta- -Diagnostic Approach

MDB CBC Chemistry Profile UA Chest & Abdominal

Radiographs Abdominal Ultrasound

Neurologic Tests EMG CSF Analysis

Cisternal Lumbar

MRI (Whole Spine)

Client EducationP

Greta- -Blood work & UA Unremarkable

O

Greta- -Chest Rads

O

Greta- -Abdominal Rads

O

Greta- -Abdominal Ultrasound

O

Greta

Differential Dx ?

Diagnostic Approach ?

Treatment ?

P

Humeral Immunity

Circulating Immune-complexes 59.3 + 2.5 µg/ml

(normal = 18.7 + 2.5 µg/ml)

Contain non- specific inflammatory proteins on electrophoresis

Cell-Mediated Immunity

Attenuated Response to Mytogens ConA Polkweed Mitogen PHA

Circulating Suppressor Cells

Greta- -EMG Needle EMG normal NCV 55 m/sec F wave present RNS- -nondecremental SEP- -abnormal

O

Greta

Spinal Cord Evoked Potential

NormalEarly DMLate DM

Greta- -CSF Analysis Cisternal CSF

Color/Transparency clear

Protein mg/dL 15

RBC/μL 1

WBC/μL 1

A cell differential count yielded the following: 1% Neutrophils 89% Lymphocytes 10% Mononuclear phagocytes

Interpretation: Benign CSF

Lumbar CSF

Color/Transparency clear

Protein mg/dL 65

RBC/μL 15

WBC/μL 2

A cell differential count yielded the following: 1% Neutrophils 85% Lymphocytes 14% Mononuclear phagocytes

Interpretation: Albuminocytologic

dissociationO

CSF Cholinesterase

normal DM inflam

*

*

O

• Greta• AO- - 250 IU/ml• Lumbar- - 560 IU/ml

Lumbar IgG Concentration

IgG

con

cent

ratio

n

DM normal

Oligoclonal Bands of IgG

Oligoclonal Bands of IgG

2-D Electrophoresis of CSF

Normal DM

CSF Inflammatory Markers

ICAM IL6 NSE Ubiq. S100 Neop.DM Mean 1.5 1.2 1.1 0.9 0.4 1.1

SD 0.7 0.6 0.7 0.9 0.5 1.0Freq. 0.9 0.9 0.8 0.6 0.4 0.7

NIFD Mean 0.8 0.3 0.7 0.3 0.2 0.8SD 0.8 0.8 0.5 0.8 0.4 1.0

Freq. 0.7 0.2 0.7 0.2 0.2 0.5

MBP assay in CSF

GSDM: 4.28 ng/ml ± 2.36

Non-Infam. ND: 0.63 ng/ml ± 0.86

(t>0.05) M

BP0

2.5

5

7.5

10

DM cont

trt

Oneway Analysis of MBP By trt

MBP/TP ratio in CSF

GSDM: 0.092 ± 0.048

Non-Inlfam. ND: 0.024 ± 0.020

(t>0.05)m

bp/tp

0

0.025

0.05

0.075

0.1

0.125

0.15

DM cont

trt

Excluded Rows 1

Oneway Analysis of mbp/tp By trt

Greta- -MRI Lumbar

O

Greta- -MRI Thoracic

O

Greta- -MRI Cervical

O

Greta- -Assessment MDB was essentially normal

Mild HD/hepato- -splenomegaly

EMG demonstrated alterations consistent with spinal white matter conduction delay

CSF showed TL Albuminocytologic dissociation consistent with chronic degenerative prosess

MRI did not reveal significant structural disease

A

Greta- -DM Flash Test

Results came back POSITIVE 96% sensitivity 99% specificity

1 2 3 4 5 6 7 8

Figure 3. DM Flash test. 1-4 are GSDM patients while 5-8 are GSD patients with other neurological diseases.

O

GRETA- -FINAL DIAGNOSISGerman Shepherd Dog

Myelopathy

A

Current Hypothesis

An Auto-Immune CNS Disease Immune-complexes damage endothelium Leads to perivascular fibrin deposition Fibrin degradation leads to leukocyte infiltration Leukocytes produce prostaglandins and

leukotreines Leads to Free-Radical production and damage

Treatment must take these steps into account

Comparison of GSDM & PPMS

GSDM Progressive spinal cord

disease with myelin & axonal loss

No sex predilection

Occurs in 4-6th decade of life

Course is 7-10 years

CSF oligoclonal IgG

Non-plaque forming

Increased CSF MBP

PPMS Progressive spinal cord

disease with myelin & axonal loss

No sex predilection

Occurs in 4-6th decade of life

Course is 7-10 years

CSF oligoclonal IgG

Non-plaque forming

Greta- -Client Education May expect gradual return to function

expecting 80% of recovery in 3 months

May continue to progress over 12-18 months

Need to monitor spleen and blood work every 6 months

Reassess as needed, changing medications when appropriateP

Greta- -TCVM exam Tongue

Pale Wet

Pulse Weak bilaterally

Sensitivity GB 21 BL 18 BL 23

TCVM Diagnosis

Combined Qi/Yin Deficiency with Stagnation

Treatment

Exercise

20-30 minutes twice a week

1 hour once a week

sustained aerobic exercise is needed

CNS O2 delivery

Treatment

Dietary Considerations

Tofu Fresh vegetables

carrots greens peppers broccoli

Ginger, garlic & mustard

Treatment

Supplements

Antioxidants Membrane stabilizers Tonics Anti-inflammatory

Treatment

Medication

Aminocaproic acid (500 mg TID)

n-Acetylcysteine (25 mg/kg TID QD for 2 weeks, then TID QOD)

Conclusion Degenerative Myelopathy appears to be

an Autoimmune Disease and Treatment must be directed at this Process.

Exercise Diet Supplements Medication

Things that CNS O2 Availability

TCVM for GSDM Treat what you see

Most cases present with Wei syndrome secondary to combined Qi & Yin Deficiency

Special AP BL-62

Herbals Di Huang Yin Zi Tang (Rehmannia Decoction) Hu Qian Tang (Hidden Tiger Powder)

Di Huang Yin Zi Tang(Rehmannia Decoction)

Shu Di Huang 10 gm Shan Zhu Yu 10 gmRou Cong Rong 10 gmBa Ji Tian 10 gm Fu Zi 10 gm Rou Gui - An Nan 10 gmShi Hu – fine 10 gmMai Men Dong 10 gmShi Chang Pu 10 gm Yuan Zhi 10 gmFu Ling – curled 10 gm Wu Wei Zi 10 gm

Powder herbs and mix thoroughly. Dosage is 0.5 gm/10lbs for 2 weeks and then 1 gm/10lbs.

Di Huang Yin Zi Tang(Rehmannia Decoction)

Rx Principle:Nourish and tonifies kidney yin; strengthens kidney

water to pacify heart fire; warm and tonifies kidney yang; and strengthen bones and sinews of lower back.

Indications:Stiffness of tongue and hoarse voice; andparalysis of

lower extremities. Dry mouth without thirst and deep weak pulses.

Contraindications:Excess conditions with rising yang.

Hu Qian Tang (Hidden Tiger Powder)

Jiu Chao Huang Bai 150 gmJiu Chao Zhi Mu 30 gmShu Di Huang 60 gmSu Zhi Gui Ban 120 gmBai Shao 60 gmHu Gu 60 gm (Substitute Chuan Niu

Xi)Suo Yang 45 gmGan Jiang 15 gmChen Pi 60 gm

Powder herbs and mix thoroughly. Dosage is 0.5 gm/10lbs for 2 weeks and then 1 gm/10lbs.

Hu Qian Tang (Hidden Tiger Powder)

Rx Principle:Nourishes yin; causes fire to descend; and strengthens bones

and sinews. Treats a atrophy disorders by drying the damp and strengthening the kidney.

Indications:Weakness in lower back and knees; deterioration of the

sinews and bones with general reduction of function; wasting of muscle of the rear legs and feet; and difficult walking. Associated with red tongue and deep, weak pulses.

Contraindications:Not for atrophy due to spleen and stomach deficiency or

invasion of damp-heat.

Greta- -TCVM Therapy AP

Cervical points BL10 GB 21

Lumbar points GV 14 Bai Hui (EA & Moxa) BL40 BL62

Other points ST 36 SP 6 LI 10 LIV 3

Herbal

Hu Qian Tang Walking Tiger

Formula Jing Tang

Di Huang Yin Zi Rehmannia Formula

for Paralysis Jing Tang

GSDM Future Stem Cell Therapy

Currently temporary effects

Epimedium Powder Spinal EA

Polypeptides Neuroregenerative

Peptide Gelsolin

Improved Diagnostics Alternatives to

SOD1 Perhaps altered

ubiquitin pathway