Definitive diagnosis of PSSM is based on histopathologic examination of muscle biopsies. There are distinctive features that include abnormally staining inclusion bodies within fast twitch fibers. Other features that may be present include muscle cell death, infiltration of white cells, regenerative fibers, and atrophy of type II fiber cells.

Treatment for acute cases is similar to that for sporadic cases of tying up: 1) ensure adequate hydration status and kidney function with intravenous fluid therapy; monitor kidney function with repeat blood chemistry analysis; 2) acepromazine is helpful in relieving anxiety and may increase blood flow, but do not use this in a dehydrated animal because it decreases blood pressure; 3) NSAIDS (nonsteroidal anti-inflammatory drugs) such as banamine or bute relieve pain and inflammation but should be used with caution in a dehydrated animal that is at risk for kidney disease; 4) rest with hand walking is of prime importance once the initial stiffness subsides.

Prevention of further episodes of rhabdomyolysis with PSSM is based on feeding diets without any grain and the addition of a fat supplement to maintain low blood glucose and insulin concentrations. A very gradual training program that includes daily exercise and ample turnout also has a significant impact on decreasing serum muscle enzymes. Longing horses for a maximum of 3 minutes the first day followed by the addition of several more minutes of walk and trot each day for 3 weeks is recommended before the horses are ridden. Box stall rest for more than 12 hours a day contributes to this syndrome. Most PSSM horses have competed successfully as pleasure and hunter horses when their diets are switched to good quality grass hay, no grain or sweet feed, and a fat supplement. A by-product of rice processing that consists of 20% fat is recommended. Vitamin E and selenium may need to be added to the diet in deficient areas; they act as antioxidants that protect muscle breakdown.

Draft breed horses have a documented form of PSSM known as EPSM. Some of these horses present with weakness and loss of muscle mass. Difficulty rising without assistance is frequently described. Some gait abnormalities include a "shivers-like" gait. The prognosis is guarded in horses with weakness and atrophy.