Bored Review NM4 - Comprehensive Clinical Guide to Inclusion Body Myositis and Inflammatory Myopathies

Initial Pathological Features: Inflammation in muscle biopsies can present with specific facial features, and may involve a lid cone or modula structure during the biopsy process.
Inflammatory Characteristics:
- Patient may exhibit necrotic inflammation.
- Nana necrotic muscle fiber inflammation is a key finding.
- Pathologists may observe cellular invasion within the muscle fibers.

General Diagnostic Framework: The diagnosis follows a step-by-step process involving clinical presentation, mandatory investigations, and supportive features.
Step 1: Clinical Presentation Criteria
- Age of Onset: Traditional criteria required the patient to be older than 50 years; however, the new criteria specify an age of 45 years or older.
- Duration: The condition is chronic, defined as at least more than one year of progressive muscle weakness.
- Creatine Kinase (CK) Levels: Typically, the CK level is less than 15 times ( $15 \times$ ) the upper limit of normal ( $\text{ULN}$ ).
- Common (Typical) Presentation:
  - Characterized by "common IBM muscle involvement pattern."
  - Involves deep finger flexion weakness.
  - Involves knee extensor weakness.
Uncommon (Atypical) Presentation Criteria:
- Age of onset less than 45 years old.
- Acute or subacute onset, or less than one year of progressive weakness.
- CK levels exceeding 15 times ( $15 \times$ ) the upper limit of normal.
- Presence of acute pulmonary edema.
- Axial weakness.
- Isolated dysphagia.
- Foot drop.
- Facial diplegia.
- Proximal limb weakness in the absence of finger flexion weakness and knee extension weakness.

Mandatory Investigation Findings:
- Evidence of endomysial lymphocytes surrounding nonnecrotic muscle fibers.
- This may occur with or without cellular invasion.
- Specific biopsy finding: nonnecrotic muscle fiber surrounded by inflammation.
Supportive Features for Diagnosis:
1. Pathology (Mitochondrial Abnormality): Identified via Mitochondrial stain, specifically the Succinate Dehydrogenase ( $\text{SDH}$ ) stain, which shows cycloid abnormal findings.
2. Laboratory Tests: Detection of anti- $cN1A$ antibodies ( $\text{anti-cytosolic 5'-nucleotidase 1A}$ ).
3. Muscle Imaging: Typical appearance on Muscle MRI or diagnostic findings on ultrasound.

Category: Definitive IBM (Common Presentation):
- Requires a typical presentation (Finger flexion weakness + knee extension weakness) PLUS mandatory investigation findings (nonnecrotic muscle fiber inflammation).
Category: Probable IBM (Typical but Partial):
- Requires finger flexion weakness OR knee extension weakness PLUS mandatory investigation findings PLUS at least one supportive investigation finding.
Category: IBM (Uncommon Presentation):
- Requires an uncommon clinical presentation PLUS mandatory investigation findings PLUS at least two out of four supportive findings.

Red Flags for Alternative Diagnoses: Certain factors suggest a diagnosis other than IBM is more likely:
- Family History: IBM is usually a sporadic disease. A positive family history of any neuromuscular disease suggests a genetic or alternative condition.
- Electromyography (EMG): Findings not consistent with IBM (e.g., lack of denervation). Expected IBM findings include positive shortwave or fibrillation.
- Specific Antibodies: Presence of myocyte-specific antibodies such as $LJO1$ (Likely referring to anti-Jo-1) or antigens associated with antisynthetase syndrome (e.g., $LUO$ ).

Liver-Specific Markers: Gamma-glutamyl transferase ( $GGT$ ) is elevated in patients with liver disease but remains normal in patients with myopathies. This makes it a specific marker for liver damage.
Shared Markers: The following enzymes can be elevated in both liver disease and muscle damage (myopathy), making them less specific:
- Alanine aminotransferase ( $ALT$ ).
- Aspartate aminotransferase ( $AST$ ).
- Aldolase.
- Lactate dehydrogenase ( $LDH$ ).
Clinical Application: If a patient has a high liver function test ( $\text{LFT}$ ) and high $GGT$ , it indicates liver damage. If $GGT$ is normal despite other elevations, muscle damage should be suspected.

Anti- $TIF1 \gamma$ (Transcriptional Intermediary Factor 1-gamma):
- Most strongly associated with malignancy (cancer) in adults.
- Patients positive for this antibody require maintenance screening for malignancy for at least three years.
- In children, it causes severe skin disease, including palmar hyperkeratotic papules and a psoriasis-like syndrome.
Anti- $Mi-2$ :
- Associated with a very benign course.
- Higher prevalence in Hispanic populations.
- Usually presents with minimal or no muscle weakness.
Anti- $MDA5$ (Melanoma Differentiation-Associated Protein 5):
- Associated with Interstitial Lung Disease ( $\text{ILD}$ ).
- Associated with cardiopulmonary syndrome.
- Clinical signs include skin ulcerations and oral restorations/ulcerations.
Anti- $NXP2$ (Nuclear Matrix Protein 2):
- Seen in pediatric/juvenile dermatomyositis.
- Associated with cancer risk, though lower than anti- $TIF1 \gamma$ .
- Associated with dysphagia.
Anti- $SAE$ (Small Ubiquitin-like Modifier Activating Enzyme):
- Characterized by skin manifestations presenting before the onset of muscle weakness.

Paramyotonia Congenita:
- Demonstrable myotonia that worsens with repetition of the eliciting maneuver (paradoxical myotonia).
- Worsens significantly in cold environments.
Myotonic Dystrophy (Type 1 and Type 2):
- Characterized by the "warm-up" phenomenon.
- Myotonia improves with the repetition of the maneuver.
Other Related Conditions: Anderson-Tawil Syndrome and Channel Myotonia possess distinct clinical behaviors regarding repetition.

Question: Which of the following serum enzymes are elevated in patients with liver disease and normal in patients with myopathies? (Options: Alanine aminotransferase, Aldolase, Aspartate aminotransferase, Gamma glutamyl transferase, Lactate dehydrogenase).
- Response: Gamma glutamyl transferase ( $GGT$ ). It is specific to the liver and not for muscle.
Question: Which dermatomyositis specific antibody is most associated with malignancy?
- Response: $TIF1 \gamma$ . Patients require at least three years of cancer screening.
Question: Which of the following conditions have demonstrable myotonia that worsen with repetition of the eliciting maneuver?
- Response: Baromyotonia (Paramyotonia congenita), due to paradoxical myotonia. Classically, myotonic dystrophy improves with repetition.