HISTORY OF PRESENT ILLNESS

OR is a 65 y.o. man with history of gout who presents for myopathy.  Patient reports symptoms started in early September 2019 when he noted decreased appetite, excessive fatigue, reduced exercise tolerance, and exhaustion along with early satiety.   Symptoms started 3-4 weeks following  a viral illness which presented with upper respiratory congestion.  No history of associated diarrhea, nausea, vomiting, fever or chills preceding symptom onset.  He was evaluated at a local clinic, initially, and an extensive workup ensued with no definite diagnosis.  Lab results are notable for positive ANA and elevated CK levels.  He developed worsening progressive dysphagia and was admitted to a local Hospital on 9/17/2019.   Myositis was suspected likely polymyositis per neurology evaluation.   Patient had EMG which reportedly demonstrated evidence myopathy.  He underwent quadriceps muscle biopsy on 9/18/2019.  Histopathology reported no clear evidence of inflammatory myositis!

 During his hospitalization in 9/2019, he was treated with IV Solu-Medrol 1 gram for 3 days.  He noted significant improvement in his fatigue level with steroid use but continues to have nasal speech and dysphagia.  He underwent speech evaluation while inpatient and elected not to have any tube feeding started at that time.  Patient was found to have acute gastric ulcers without hemorrhage along with superficial duodenal ulcers.  Endoscopy also showed Schatski's ring.  Started on PPI. 

Patient's hospital stay was also complicated by nonsustained supraventricular tachycardia, echocardiogram was obtained; unremarkable.  He was started on metoprolol 25 mg twice daily.  He was discharged on long-term taper of prednisone 60 milligrams daily with plan to taper down to 50 milligrams in 1 week followed by 40 milligrams daily. 

Following his discharge from the hospital, he had outpatient evaluation by rheumatologist on 10/2/2019 who recommended to coordinate care with neurology and started him on methotrexate subcutaneous injection 15 milligrams weekly.   Patient took 1 dose of MTX and decided to discontinue it as he was concerned for increased CK level and elevated liver enzymes.

He saw PCP on 10/7/2019 for ongoing dysphagia and continued worsening symptoms with prednisone 40mg.  Patient was unable to keep up with his nutrition intake and reported coughing at night.  He has to sleep in a chair.  At this time he is unable to eat thick liquid consistency like soup.  His oral prednisone dose increased from 40 milligrams daily to 60 milligram daily at that visit.  He also reported that his voice sounded nasal and felt always congested.  He developed oral thrush.

He was revaluated by rheumatology on 10/17/19 at a tertiary care hospital who recommended admitting the patient.  He was admitted the same day.   He received Solumedrol 1g daily x 3 and IVIG 50g-50g-30g.  Discharged on 10/31 on Cellcept 500 mg PO BID and prednisone 60mg daily.  Since his discharge he feels better.  His strength has improved in upper and lower extremities.  His dysphagia is stable, but he has a G-tube for nutrition. Rheumatology increased the Cellcept to 1000 PO bid today. 

Past Medical History:  Gout, Immune deficiency disorder (CMS/HCC),  Sleep apnea 

Past Surgical History: HERNIA REPAIR , IR G Tube Placement TBD in OR 10/30/2019, MUSCLE BIOPSY LEFT BICEPS.

Family History : Anxiety disorder in Sister.  Anxiety disorder Brother.  No neuromuscular disease in his family.

Social History:  Socioeconomic History:  Marital status: Not on file 

Occupational History : Not on file 

Smoke: No

Alcohol: Beer once a month

No drugs

Used to work on pharmaceutical company. He is a chemist. Now on disability 

ALLERGIES/INTOLERANCES

No Known Allergies

HOME MEDICATIONS

cholecalciferol (VITAMIN D3) 1,000 unit tablet Administer 1 tablet (1,000 units) via gastrostomy tube once daily. 10/31/19 Yes 

lansoprazole (PREVACID SOLUTAB) 30 mg disintegrating tablet Administer 1 tablet (30 mg) via gastrostomy tube once daily, 30 min prior to meal. 10/31/19 1/23/21 Yes 

melatonin 3 mg tablet Administer 1 tablet (3 mg) via gastrostomy tube at bedtime as needed (insomnia). 10/31/19 Yes 

multivitamin with iron (TAB-A-VITE W/IRON) tablet Administer 1 tablet via gastrostomy tube once daily. 10/31/19 1/23/21 Yes 

mycophenolate mofetil (CELLCEPT) 200 mg/mL suspension Take 5 mL (1,000 mg) by mouth every twelve hours. 12/2/19 2/24/21 Yes 

predniSONE (DELTASONE) 20 mg tablet Adminster through G-Tube 50 mg daily x 4 weeks then take 40 mg daily x 4 weeks then take 30 mg daily x 4 weeks then take 20 mg daily 12/2/19 Yes 

sulfamethoxazole-trimethoprim (BACTRIM) 200-40 mg/5 mL suspension Administer 20 mL (160 mg of trimethoprim per DOSE) via gastrostomy tube three times a week on Monday, Wednesday, and Friday for 90 days. 11/1/19 1/30/20 Yes 

REVIEW OF SYSTEMS: Pertinent positive and negative systems are described in the HPI; the remainder of the 14 systems are negative.

OBJECTIVE

VS

BP (!) 93/50 | Pulse 62 | Ht 1.702 m (5' 7") | Wt 74.4 kg (164 lb) | BMI 25.69 kg/m² 

Physical Exam

GENERAL: Well-appearing, in no apparent distress

HEENT: MMM, no scleral icterus

NECK: Supple and without palpable lymphadenopathy

EXTREMITIES: WWP, no edema, cyanosis, or clubbing

Neuro Exam

MENTAL STATUS: Alert, interactive, cooperative; Language fluency and comprehension intact

CRANIAL NERVES: PERRL, ocular pursuits and saccades full and smooth, no ptosis; Facial sensation intact and symmetric to light touch bilaterally over all 3 divisions; Smile, lip closure, cheek puff, eyebrow raise, and eyelid closure strong and symmetric; Normal hearing to conversation; Palate elevates symmetrically, uvula midline, nasal voice, mild difficulty with pa-pa; Shoulder shrug 5/5 strength bilaterally, head rotation and neck flexion 5/5 strength bilaterally; Tongue protrudes in the midline, no atrophy or fasciculations

MOTOR: Muscle bulk - normal and symmetric; Involuntary movements - none; Tone - no spasticity, rigidity, or flaccidity;

Strength Right/Left 

Shoulder abduction 4/5 4/5 

Elbow flexion 4+/5 4+/5 

Elbow extension 5/5 5/5 

Wrist flexion 5/5 5/5 

Wrist extension 5/5 5/5 

Finger extension 5/5 5/5 

Finger abduction - FDIH 5/5 5/5 

Finger abduction - ADQ 5/5 5/5 

Thumb abduction 5/5 5/5 

Hip flexion 4+/5 4+/5 

Knee flexion 5/5 5/5 

Knee extension 5/5 5/5 

Ankle dorsiflexion 5/5 5/5 

Ankle plantarflexion 5/5 5/5 

SENSORY: Sensation to pinprick intact and symmetric throughout bilateral upper and lower extremities; Sensation to vibration 12s at bilateral great toes

REFLEXES: Right Left 

Biceps 2/4 2/4 

Brachioradialis 2/4 2/4 

Triceps 2/4 2/4 

Patellae 2/4 2/4 

Calcanei 2/4 2/4 

Plantar responses Flexor Flexor 

COORDINATION: No dysmetria on finger-nose-finger or heel-knee-shin bilaterally

GAIT: Able to rise from seated position and deep knee bend without use of UEs; Walks with narrow base and normal heel strike, ankle dorsiflexion, hip flexion, hip extension, stride length; Able to walk on toes, heels, and in tandem

Studies and Imaging

Personally reviewed, significant for:

10/27/19

- Myasthenia panel negative 

10/17/19

- Myomarker 3 panel: Positive Anti-NXP2 (111 - normal <20)

- Anti HMG Coa Ab, SRP Ab negative

CK trend

- 9/11/19: 3507

- 9/14/19: 5386

- 10/17/19: 2455

- 10/18/19: 1339

- 10/19/19: 718

- 10/25/19: 294

- 11/7/19: 86

- 11/20/19: 65

10/10/19: Elevated AST 157, ALT 103, normal creatinine 1.21, elevated CK level 1428, elevated aldolase 11.9, WBC 9.1, hemoglobin 16.5, platelets 188, slight lymphopenia ALS 0.4, elevated C-reactive protein 21.5, sed rate normal at 17. Normal TSH level I.93

Summary of OSH radiographic data reviewed and pertinent for:

9/19/2019 video fluoroscopic swallowing study at  radiology: Demonstrated normal oral bullous formation. No oral delay. Nasopharyngeal reflux with nectar consistency barium. Transient tracheal aspiration with thin and nectar consistency barium with cough response. Mild pharyngeal residual, worse with thinner consistencies. There is no epiglottic inversion.

 CT abdomen and pelvis with IV contrast 9/14/2019: Demonstrated possible mild fatty change of the liver. No hydronephrosis. Overall unremarkable.

CT chest on 10/18/2019:  Pattern of nonspecific interstitial pneumonitis in keeping with interstitial lung disease secondary to connective tissue disease/autoimmune disease.  

More focal posterior basilar consolidation may represent superimposed aspiration or infection. 

CT head without IV contrast 9/8/2019: No acute intracranial abnormality. 

EMG 9/2019 reveals electrophysiologic evidence of a myopathy with inflammatory components. Personally reviewed in care everywhere.

 Summary of pathology data available for review include:  Muscle biopsy (left quadriceps surgical biopsy ) 9/18/2019: Demonstrated denervation atrophy, slight. Type I fiber atrophy. Nonspecific abnormalities.*Increased internalized nuclei and granular glycogen deposits, raising the question of an inherited muscular dystrophy. 

 Muscle biospy:  Repeat BMBx 10/21:

Diagnosis: A-C. Skeletal muscle, left deltoid, biopsy:  Active myopathy with features suggestive of an inflammatory myopathy; see  comment.   - Electron microscopy studies are in progress. A supplemental report will be issued when the results are available in 2 to 3 weeks.     

Comment: This biopsy shows active myopathic changes in the form of  regenerating/degenerating fibers, most notably on the frozen material in an area with frequent degenerating fibers, marked perimysial and endomysial  fibrosis, and numerous macrophages, but no significant lymphocytic inflammation. There is mild, diffuse upregulation of MHC-I in muscle fibers, patchy increased complement expression in endomysial capillary walls and some degenerating fibers, but no definite increase in COX-negative fibers. While numerous degenerating fibers show vacuolar spaces containing basophilic material, these are not definitive for rimmed vacuoles and could be due to the degenerative process. Prior steroid treatment may have reduced the amount of lymphocytic inflammation in the biopsy.  Overall, these features support the diagnosis of an active myopathy with features suggestive of an inflammatory myopathy.  Notably, the majority of these features were not present in the prior left quad biopsy performed in September, 2019 (Reviewed at U-M Neuropathology, case# OC-19-27528). 

The exact etiology of these changes is not clear from this biopsy, and the differential includes a number of inflammatory myopathies, including  necrotizing autoimmune myopathy (NAM), antisynthetase syndrome, dermatomyositis, inclusion body myositis, and so-called 'overlap myositis' 

(Reference 1). NAM can present as a necrotizing myopathy without a distinct pattern of damage, only mild inflammation, and scattered fibers with C5b9 positivity; follow-up of serum anti-SRP results is suggested to evaluate for this possibility.  Serum Anti-Jo-1 testing was negative, but the histologic features of this biopsy material could be compatible with anti-synthetase syndrome due to a non-Jo-1 autoantibody.  The capillary C5b9 deposition and perifascicular accentuation of CD56 staining seen in this case can be seen in dermatomyositis (Reference 2), however there is no definitive perifascicular atrophy. There are no definitive rimmed vacuoles, strong diffuse MHC-I staining, defininte increase in COX-negative fibers, or TDP-43 positive inclusions to support a diagnosis of inclusion body myositis, but this possibility can not be entirely ruled out based on the biopsy results. Clinical correlation with the results of the MyoMarker Panel 3 Plus panel may be helpful in differentiating between these possibilities. 

Electron microscopic analysis will be performed to assess for tubuloreticular inclusions seen in dermatomyositis, myonuclear actin filaments reported in antisynthetase syndrome, and tubulofilamentous inclusions that can be seen in inclusion body myositis. The results will be reported in a supplemental report in approximately 2-3 weeks.   

ASSESSMENT

OR is a 65 y.o. female with past medical history significant for gout who presents to Tertiary care Neuromuscular Clinic for inflammatory myopathy. 

He developed proximal weakness and dysphagia in September 2019 after 3-4 weeks of a viral upper respiratory infection. His symptoms initially improved with steroids but worsened again once the prednisone was at 40mg. His highest CK has been in the 5000s. He was admitted to TCC on October and received IV solumedrol and IVIg after which his strength improved. However, his dysphagia persisted reason why he had a G-tube placed. He was discharged on prednisone 60mg and cellcept 500/1000. Since discharge, his proximal strength have greatly improved but his dysphagia has not. Regarding his work up, his initial left VL biopsy had non-specific changes, but his left deltoid biopsy was consistent with an inflammatory myopathy. Prior EMG was consistent with myopathy and his CK has been normal for the past month. His myomarker 3 panel showed a positive Anti-NXP2, otherwise unremarkable. Anti HMG Coa and SRP Ab were negative.

On today's exam, he had a nasal voice with mild flaccid dysarthria. Has difficulties swallowing and had proximal weakness (upper > lower) which seems improved in comparison to his inpatient exam. 

His presentation, labs, biopsy and improvement after steroids are consistent with an inflammatory myopathy. The exact etiology of his myopathy is unclear, but likely may be immune mediated and differential diagnosis includes immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome and viral myositis.  The fact that there were numerous macrophages, but no significant lymphocytic inflammation in his biopsy, along with the aggressive and rapid presentation involving proximal and pharyngeal muscles makes IMNM a very strong possibility.  anti-SRP and HMG CoA Ab are negative, so this is most likely a seronegative IMNM case.  A Non-Jo-1 autoantibody Antisynthetase syndrome is possible, especially if you take into account interstitial lung disease findings reported on CT chest. The biopsy findings can be consistent with this as well.  The positive NXP-2 may be significant with dermatomyositis which does not seem consistent with the patient's presentation.  Even though the capillary C5b9 deposition and perifascicular accentuation of CD56 staining seen in this case can be seen in dermatomyositis, there is no definitive perifascicular atrophy to support a dermatomyositis diagnosis.

Viral myositis is in the differential too. However, I would expect a monophasic event instead of episodes of improvement and worsening, which makes this less likely. He has a flaccid dysarthria and nasal voice which raised a concern for a superimposed neuromuscular junction problem, but his myasthenia panel is negative and therefore, this is most likely secondary to the underlying inflammatory myopathy. 

Rheumatology is primarily managing this patient. They will slowly taper the prednisone, increase the Cellcept to 1000 bid and start IVIG every 4 weeks. If this is indeed IMNM, CK tends to correlate very well with disease activity. The trial of IVIg will be primarily to see if there will be an improvement with the dysphagia. 

PLAN

• Continue Cellcept 1000mg BID

• Agree with slow prednisone taper. IVIg every 4 weeks (recommend 1g/kg every 4 weeks) 

• Speech and swallow therapy

• OK to exercise. Should gradually increase the activity level. 

• Follow up as needed since the patient is being primarily managed by rheumatology. 

IMPRESSION:   OR 65 year-old, man who developed nontraumatic rhabdomyolysis with subacute onset proximal muscle as well as bulbar weakness, following a recent viral upper respiratory tract infection.  He has positive immunological markers.  EMG/NCS of his right lower extremity showed a myopathic disease process with marked membrane irritability in the right iliopsoas muscle.  Muscle biopsy from his left vastus lateralis muscle indicated denervation changes and type I atrophy, but no inflammatory cells.  His CK level trended down after patient was started on corticosteroids.  His LFTs are deranged (elevation of AST, ALT, GGT) and some CK elevation can be accounted to this.  His aldolase which was elevated earlier has now trended down.  Elevated aldolase can be seen in perimysial pathology and fasciitis.

 On his examination today, and his lower extremities he has proximal weakness in his hip flexors/extensors, abductors/adductors.  His knee extensor (quadriceps) strength is 5/5 (normal).  Prior to the muscle biopsy, the examination done in hospital indicates that his knee extensors were clinically weak muscles.  If so, it is less likely that the muscle biopsy was a sampling error.  A repeat muscle biopsy (Deltoid - clinically weak) can be considered, however.  Denervation changes in the muscle is a neurogenic process.  However, type 1 atrophy is seen in few conditions including denervation with type 1 fiber atrophy with a slow-to-fast fiber type shift. It can also be seen in myotonic dystrophy (clinically not present in patient), metabolic myopathies and congenital myopathies.  In congenital myopathies the CK is either normal or mildly elevated, while in metabolic myopathies such as primary or secondary carnitine deficiencies it is markedly elevated.  Again, it is unlikely given no prior similar episodes in the past.  Also, he does not demonstrate a dilated or hypertrophic cardiomyopathy on echocardiogram, as can be seen in carnitine deficiencies.  Viral related myositis is usually self-limited requires only supportive therapy.  Patient's clinical condition has not improved and he has persistent bulbar weakness which is concerning.

Immune mediated myopathy (HCC-CMS) [M33.22]  NXP2-ab.  Regardless of the muscle biopsy, his clinical picture appears like an autoimmune inflammatory myopathy, post-infectious, triggered by viral (EBV) syndrome.  DDx: IMNM (immune-mediated necrotizing myopathy). 

With regards to pramipexole and rhabdomyolysis.  A single case of rhabdomyolysis is reported and has occurred in a 49-year-old male with advanced Parkinson's disease treated with Pramipexole dihydrochloride tablets. [https://www.sandoz.ca/sites/www.sandoz.ca/files/Pramipexole%20Product%20Monograph.pdf}

Caution regarding concomitant use of methotrexate (high-dose) with PPI.  Concomitant use of proton pump inhibitors with methotrexate (primarily high-dose methotrexate) may lead to elevation and prolongation of serum methotrexate levels and metabolite (hydroxymethotrexate) levels (based on case reports and pharmacokinetic studies). 

 Of note, there are positive association of EBV infection with PM/DM, especially in those with nasopharyngeal carcinoma, reported in literature. [Chen DY, Chen YM, Lan JL, et al. Polymyositis/dermatomyositis and nasopharyngeal carcinoma: the Epstein–Barr virus connection? J Clin Virol 2010; 49:290–295.]

RECOMMENDATIONS:

• IVIG can be used in the treatment of refractory myositis.  IVIG 2 g/kg over 5 days (0.4 g/kg/day x 5 days) in combination with prednisone 60 mg PO QAM after meal and assess response.  This treatment is to be maintained until patient is back to normal strength or until improvement in strength has reached a plateau.  Following this a slow taper of prednisone by 5 to 10 mg every 4 weeks can be initiated.  Once the dose is reduced to 20 mg every other day, taper by 2.5 to 5 mg every 2 weeks.

• Continue PPI or start H2 blockers.

• Low sodium, low-carbohydrate, high protein diet to avoid excessive weight gain, while on steroids. 

• QuantiFERON-TB Gold Plus test.

• Bactrim for pneumocystis prophylaxis.

• Baseline DEXA scan.

• Calcium supplementation of 1 g/day and vitamin D 800 IU/day for prophylaxis against steroid-induced osteopenia.

• Monitoring electrolytes and replacement of potassium PRN. 

• Monitoring blood glucose

• Monitoring blood pressure

• Ophthalmology evaluation to check for glaucoma and cataracts. 

• Monitor response based on objective clinical examination, and myopathy questionnaire score.

• Monitor serum CK levels.

• Necrotizing myopathy panel (Mayo): anti-HMGCR-ab and anti-SRP.

• Myositis-Specific Antibodies. They are highly specific for patients with PM, DM, anti-synthetase syndrome, necrotizing myositis, and overlap syndromes: Anti-Jo-1, Anti-PL-12,  Anti-PL-7, Anti-OJ, Anti-EJ, Anti-SRP (part of necrotizing myopathy panel), Anti-Mi-2, Anti-TIF-1gamma/TIF-1alpha, Anti-MDA5, Anti-NXP-2 (MJ).

• Anti-AChr-ab (MG eval).

• Muscle biopsy (Deltoid) can be considered following MRI of upper limbs to check for signal changes to obtain better yield.

• Physical Therapy.

A 57-year-old woman presented for a neurologic consultation reporting 2 to 3 months of mild proximal muscle weakness of her legs and arms.  Upon questioning, she reported myalgia, fatigue, and a 15-lb weight loss in the preceding few months but denied fevers, cough, or arthralgias.  She also had recent mild erythema on her face that she attributed to sun exposure.  She was healthy and active at her baseline.

On examination, she was found to have erythematous skin changes on her scalp, malar region of her face, eyelids, anterior neck (V sign), elbows, and metacarpophalangeal joints (Gottron sign).  On strength testing, she had weakness predominantly in the following areas: neck flexors 4+/5, shoulder abductors 4/5, elbow flexors and extensors 4/5, hip flexors 4/5, and knee extensors 4+/5.

Her creatine kinase level was mildly elevated at 389 U/L. Needle EMG showed fibrillation potentials with short-duration, low-amplitude motor unit potentials and an early recruitment pattern in proximal muscles.  Biceps muscle biopsy showed inflammatory cells, necrosis, and atrophy in a perifascicular distribution. Myositis antibody panel was positive for anti–nuclear matrix protein 2 (NXP-2) antibody. CT of the chest, abdomen, and pelvis and mammogram were negative for malignancy. The patient was diagnosed with dermatomyositis based on her clinical presentation of proximal muscle weakness, erythematous skin rash on sun-exposed regions, and muscle biopsy hallmark feature of perifascicular atrophy.  She was started on oral prednisone and methotrexate, but her symptoms continued to worsen. Given the increased association of malignancy and anti–NXP-2 antibody, despite her negative routinemalignancy workup, a positron emission tomography (PET) scan was performed, which revealed a nasal mass found to be a nasopharyngeal carcinoma.  She received radiation and  chemotherapy for the tumor, was placed on intravenous immunoglobulin (IVIg), prednisone, and methotrexate with improvement in her strength, and continued to be under surveillance 3 years later.

Comment:  This case exemplifies the increased risk of malignancy associated with the anti–NXP-2 antibody found in patients with dermatomyositis and the importance of vigilant cancer screening because it impacts the treatment and prognosis of these patients.

A 51-year-old woman presented with more than 5 months of joint pain and fatigue followed by weakness with difficulty arising from a chair.  Within a few months, her muscle weakness had progressed and was accompanied by shortness of breath with exertion and a nonproductive cough.  She denied any history of rash but reported mild dry, cracking skin changes on her fingertips.  Her past medical history was notable only for hypertension.  

Her neurologic examination revealed proximal muscle weakness of her deltoids and biceps (4/5) and hip flexors (4/5).  Examination of her skin showed no erythematous rash over her face or joints but did show signs of mechanic’s hands.  Her creatine kinase (CK) level was 942 U/L.  EMGshowed diffuse, small, myopathic units with early recruitment and fibrillation potentials.  Muscle biopsy of the biceps showed necrosis in the perifascicular region and fragmentation of the perimysium.  Testing for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase antibody was negative, but the myositis antibody panel was positive for anti–Jo-1 antibody.

The patient was diagnosed with antisynthetase syndrome because she had the constellation of clinical features of myositis, arthralgia, mechanic’s hands, and pulmonary symptoms. She was found to have anti–Jo-1 antibody, which has a high association with myositis and lung involvement.  CT of her chest showed findings of interstitial lung disease.

Methotrexate was avoided because of concern for pulmonary toxicity; thus, she was started on prednisone 40 mg daily and azathioprine at 50mg a day, titrated to 75 mg 2 times a day (within 6 weeks), with normalization of her strength and CK level within 9 months.

COMMENT:  This case portrays the constellation of clinical features seen in antisynthetase syndrome; in addition to the myositis, patients are found to have joint involvement and, importantly, interstitial lung disease, which can be the main prognostic factor.  Diagnosis is aided by the identification of one of the antisynthetase autoantibodies, and patients often improve with long-term immunosuppressive therapy.