NEUROMUSCULAR CASE OF THE MONTH - DECEMBER 2002

A case of ACTH induced type 2 fiber atrophy?
Contributed by Drs. Giunio Bruto Cherubini and Rodolfo Cappello
Royal Veterinary College
London, UK


Clinical History
A 4 year old female spayed chocolate Labrador Retriever was referred with a 6-8 month history of progressive panting, ataxia and weakness. Clinical signs worsened over the 4 weeks prior to presentation. Muffin also had a history of skin problems.

Physical and Neurological Examination
The physical examination was unremarkable with the exception of small areas of alopecia on the distal surface of all 4 limbs. Neurological examination revealed severely decreased spinal reflexes, reduced postural reactions, and dimished proprioception in all four limbs. Facial sensation, corneal and palpebral reflexes were reduced bilaterally. The neuroanatomical localization was the lower motor neuron system. Differential diagnosis included anomalous, metabolic, immune-mediated, infectious, inflammatory, idiopathic, neoplastic and degenerative diseases.

Diagnostic Testing
CBC & serum Chemistry – No significant abnormalities
Toxoplasma gondii antibody - Negative
Neospora caninum antibody – IFA 1/50
TSH – 0.28(<0.41 ng/ml)
T4 – 23.9 (13-52 nmol/l)
Cortisol - 293 (20-250nmol/l)
Cortisol - post ACTH – 939 (<600 nmol/l)
CSF – No significant abnormalities
Electromyography including motor nerve conduction velocity - No abnormalities

Interpretation: These results were suggestive of a peripheral neuromuscular disorder possibly secondary to hyperadrenocorticism. The dog was examined again 2 weeks later.

Abdominal Ultrasound – R. Adrenal glands 1.92 x 0.64 x 0.48 cm
                                    L. Adrenal glands 1.94 x 0.45 x 0.52 cm
                                    Liver mild hepatopathy

Endogenous ACTH – 278 (20-80 pmol/l)

Interpretation: The size of the adrenal glands was within the reference range. Endogenous ACTH was elevated.

Muscle and Nerve Biopsies
L. gastrocnemius, L. cranialis tibialis and L. paralumbar muscles were evaluated. All three muscles were similar in appearance. The normal mosaic pattern of muscle fiber types was present. Intramuscular nerve branches were normal in appearance. Type 2 fibers were smaller than type 1 fibers consistent with type 2 fiber atrophy. Type 2 fiber atrophy is consistent with either recent corticosteroid therapy or an endocrine disorder such as hypothyroidism or Cushing’s syndrome. There was mild depletion of large myelinated nerve fibers within the nerve specimen with subperineurial edema.


Figure 1. (H&E stain)


Figure 2. ATPase reaction;
pH 4.3 (type 2 fibers light)


Figure 3. Peroneal nerve biopsy
(Toluidine blue acid fuschin)

Second re-examination 2 weeks later

CBC & Serum Biochemistry – No abnormalities detected
LDDT: Cortisol                     84   (<250 nmol/l)
Cortisol 3 hr post Dex.      < 20   (suppress cortisol by 50%)
Cortisol 8 hr post Dex.      < 20   (suppress cortisol to below 40)

MRI- No convincing abnormalities of the Pituitary gland identified. However, the gadolinium uptake was increased.


Figure 4. T1

Figure 5. T1 post gadolinium

Figure 6. T1

Figure 7. T1 post gadolinium



Figure 8. T2



Figure 9. T2

Conclusion
Unfortunately following anesthesia for MRI, the dog developed status epilepticus that was difficult to control with anticonvulsants. The dog was again anesthetised and ventilated for 24 hours. Ventricular bigemini, hyperthermia, and respiratory distress were present. A respiratory pneumonia developed and after 6 days, the dog died. The owner declined a post mortem examination.

The laboratory results in this case are contradictory. The high level of ACTH and basal cortisol were suggestive of hyperadrenocorticism. However, the low dose dexamethasone suppression test revealed normal values, thus, ruling out a Cushing’s syndrome. Although there was increased uptake of gadolinium, the MRI findings did not show convincing signs of pituitary gland anomalies such as macroadenoma.

Hypothesis
Is the type 2 fiber atrophy related to an increased ACTH level? In a review, Anagnos et al speculated about the possibility of an ACTH induced myopathy. In fact patients treated for Cushing disease one year after adrenalectomy and receiving glucocorticoid replacement developed myopathic syndromes. Excessive amounts of ACTH can impair neuromuscular transmission by decreasing the quantal content of the end-plate potential. ( Anagnos A, Ruff RL, Kaminski HJ. Endocrine neuromyopathies. Neurol Clin. 1997 Aug; 15(3): 673-96). ACTH may have myopathic actions that are separate from those of glucocorticoids.

Any other suggestions? Comments welcome; please contact Dr Giunio Bruto Cherubini (gbcherubini@rvc.ac.uk)

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