CME INDIA Case Presentation by Dr. Sudhir Kumar, MD, DNB, DM, Pulmonology(PGI), Director, Ramkrishna Chest Hospital, Patna.

CME INDIA Case Study

Was it TIA? It Became Difficult Because of Late Diagnosis.

  • 80-year-old man, with history of Type2 diabetes, hypertension and hypothyroidism developed weakness in neck and unable to hold his head, chin coming down towards chest.
  • Initial physician consultation suggested for neck belt for holding the chin and head.
  • After physiotherapy-50% improvement in two weeks.
  • Seven days back treating physician noticed tremors in his upper limb while eating.
  • Later marked Tremors in upper limbs with transient speech problem was noticed which resolved shortly.
  • He was unable to walk, unable to chew, unable to hold head and had left ptosis,
  • He complained of severe weakness in body too.
  • Morning better, evening worse.

Past Medical History

  • History of hypertension for 25 years on Chlorthalidone, Nifedipine retard and Atenolol.
  • Hypothyroidism for last 10 years on Eltroxin.
  • Discolouration of lips 10 years back.
  • Diabetes for last 5 years on Gliclazide and Teneligliptin.
  • 3 years back received Intraocular injections for Retinopathy.
  • Osteoarthritis of knees.
  • Loss of weight for 2 months.

Recently what happened?

  • Left sided ptosis for past five months followed by head drop for past three months.
  • Drooping of chin and head for 3 months/Difficulty in getting from sitting position for 1 month.
  • Loss of appetite – fears eating/transient slowing of speech/Impaired tongue movement/Dryness of mouth/difficulty in salivation /Difficulty in chewing.
  • Progressive weakness in walking slowing of movement for 3 months.
  • Mild /slight change in signature /handwriting noticed on 21/8/21.
  • Tremor in both upper limbs on movement for task like eating with spoon.
  • Dyspnoeic of effort.

Initial Diagnosis

  • When one day patient developed sudden dysarthria, and was unable to eat and drink, he was evaluated at Bokaro. CT Scan Brain showed only age-related atrophic changes.
  • TIA (Transient Ischaemic Attack was thought by the Neurologist).

His paradoxical breathing prior to hospitalisation due to intercostal muscle weakening with diaphragmatic muscle sparing 👆

Was it TIAs?

  • When I made a detailed history of previous five months with salient points I myself diagnosed him as myasthenia gravis.
  • It was confirmed by tests and the neurologist at Patna.
  • As told by the neurologist there are only three differential diagnosis for head drop syndrome.
    1. Amyotrophic lateral sclerosis
    2. Myasthenia gravis
    3. Polymyositis/genetic myopathies
  • All three D/D I had made in the history before meeting neurologist at Patna even though I had no idea about head drop syndrome.
  • Initially he was down sliding fast because of natural history and went into respiratory failure during first three days of hospitalization.
  • was because of bulbar palsy and not because of TIA as provisionally diagnosed by initial physician(Neurologist)

Investigations

  • Acetyl Cholin receptor antibody: Positive and raised
Rare Case of Autoimmune Target of Muscle and Heart. Was it TIA?
  • Anti-musk antibody negative
Rare Case of Autoimmune Target of Muscle and Heart. Was it TIA?
  • CPK negative
  • Vit B3 – Normal
  • Vit b 12 – Normal
  • CT Lung – No evidence of thymoma
  • CRP – Normal
  • PSA – Normal
  • LFT/RFT – Normal
  • Serum protein electrophoresis – Normal
  • Comprehensive paraneoplastic antibodies test all negative
Rare Case of Autoimmune Target of Muscle and Heart. Was it TIA?
Rare Case of Autoimmune Target of Muscle and Heart. Was it TIA?
Rare Case of Autoimmune Target of Muscle and Heart. Was it TIA?

On this basis, dilated cardiomyopathy and ischaemic cause of myopathy and left ventricular dysfunction was ruled out 👆

Treatment Given

  • Pyridostigmine (180mg) SR
  • Prednisolone 20 mg od,
  • Received 150 mg of total iv immunoglobulin in last week of September 2021
Rare Case of Autoimmune Target of Muscle and Heart. Was it TIA?

Final Diagnosis

  • Detailed clinical history was quite evident for diagnosing myasthenia gravis(MG)
  • It was supported by investigations
  • It was not ischemic Cardiomyopathy
    • Also, cardiomyopathy with left ventricular dysfunction was erroneously diagnosed as dilated and ischaemic.
    • Finally, it was diagnosed as autoimmune induced non-dilated cardiomyopathy with Left ventricular dysfunction.
    • Failure promptly improved on oral steroids and iv immunoglobulin. EF rose from 30% to 50-55% within seven days.
    • On the top of it was diagnosed on the basis of characteristic and peculiar findings on ECHO itself.
    • It was later on confirmed on cardiac MRI.
Rare Case of Autoimmune Target of Muscle and Heart. Was it TIA?

Course

  • Now he is able to eat, appetite improved. Able to walk around and can take self-care of himself.
  • Earlier he was not even able to take sides while lying down in hospital bed. He was forced to pass stool and urine in bed only for first ten days.
  • Waxing waning of weakness of myasthenia gravis.

Dr. Ujjawal Roy, DM, Neuro, Ranchi:

CME INDIA Learning Points

  • Autoimmune Targets of Heart and Skeletal Muscles in Myasthenia Gravis has been described in literature.
  • Autoimmune-mediated myocarditis and/or myositis usually develops especially in thymoma-associated MG.
  • In present case occurrence of granulomatous cardiomyopathy and MG make it a rare presentation.
  • Clinical Pearls:
    • Be alert for fluctuating weakness that is more prominent in the afternoon usually involving muscles of the eyes, throat, and extremities.
    • The distinguishing clinical feature of MG is the fluctuating muscle weakness that varies in severity, worsens with physical activity, and improves with rest. It can be precipitated by
      1. Infections,
      2. surgery,
      3. Immunization,
      4. heat,
      5. Emotional stress,
      6. Pregnancy, drugs (commonly aminoglycosides, fluoroquinolones, beta-blockers, neuromuscular blocking agents),
      7. Worsening of chronic medical illnesses.
    • Do ask about the timing of the symptoms, at what time of the day do the symptoms usually occurs, as well as improvement with rest.
    • Do inquire about subtle signs like coughing after swallowing, increase time to finish eating, hoarseness of the voice, easy fatigability in the climbing upstairs, and slow and frequent errors in writing or typing.
    • Remember these symptoms are most prominent at the end of the day or work shift.
  • The most common symptoms include the following:
    • Extraocular Muscle Weakness: Around 85% of patients (diplopia, ptosis, or both.
    • Bulbar Muscle Weakness: This can be the initial presentation in 15% (difficulty chewing or frequent choking, dysphagia, hoarseness, and dysarthria.)
    • The involvement of facial muscles causes an expressionless face, and neck muscle involvement causes a dropped-head syndrome.
    • Limb Weakness: This usually involves the proximal muscles more than distal muscles, with the upper limbs more affected than the lower limbs. 
  • MuSK MG 
    • It has clinical features that are quite different from n-AChR MG.
    • More common in females, relatively spares extraocular muscles, and commonly involves bulbar, facial, and neck muscles.
    • Myasthenic crisis is also frequent in the MuSK MG.
  • Why it occurs?
    • Myasthenia gravis is the most common disorder affecting the neuromuscular junction (NMJ) of the skeletal muscles.
    • The reduced transmission of electrical impulses across the neuromuscular junction due to the formation of autoantibodies against the specific postsynaptic membrane proteins consequently causes muscle weakness.
    • The commonly implicated proteins in the NMJ against which autoantibodies are produced include:
      • Nicotinic acetylcholine receptors (n-AChR’s),
      • Muscle-specific kinase (MuSK), 
      • Lipoprotein-related protein 4 (LPR4).
    •  Approximately 10% of patients with MG have a thymoma, and it is implicated in the production of autoantibodies.

Myasthenia Gravis Classification

Early-onset MG: Age at onset less than 50 years with thymic hyperplasia
Late-onset MG: Age at onset greater than 50 years with thymic atrophy
Thymoma-associated MG
MG with anti-MuSK antibodies
Ocular MG: Symptoms only from periocular muscles
MG with no detectable AChR and MuSK antibodies

How to investigate?

Serologic Tests:

  • The anti-AChR Ab test is very specific, and it confirms the diagnosis in patients with classical clinical findings.
  • About 5% to 10%, will demonstrate anti-MuSK antibodies.
  • Only in a few sporadic cases, both anti-AChR and anti-MuSK antibodies are present in the same patient.
  • The 3% to 50% of the remaining patients who are seronegative to either of these antibodies will demonstrate anti-LRP4 antibodies.
  • Anti-striated muscle antibodies are present in 30% of MG patients. They are more useful as a serologic marker for thymoma, especially in younger patients.

Electrophysiologic Tests: 

  • These are relevant in patients who are seronegative for antibody testing. Commonly employed tests for MG are the repetitive nerve stimulation (RNS) test and single-fiber electromyography (SFEMG).
  • Both the tests assess for conduction delays in the NMJ.
  • Routine nerve conduction studies are usually performed to determine the functioning of the nerves and muscles before undertaking these tests.

Edrophonium (Tensilon) Test:

  • Edrophonium is a short-acting acetylcholinesterase inhibitor that increases the availability of ACh in the NMJ. This is particularly useful for ocular MG, where electrophysiologic testing cannot be performed.
  • It is administered intravenously, and the patient is observed for improvement in the symptoms of ptosis or diplopia.
  • It has a sensitivity of 71% to 95% for MG diagnosis.

Ice-pack Test: 

  • When edrophonium testing is contraindicated, an ice-pack test can be performed.
  • This test requires an ice-pack placed over the eye for 2-5 minutes.
  • Then, an assessment for any improvement in ptosis is done. This test cannot be used for the evaluation of extraocular muscles.

Imaging: 

  • Chest computed tomography (CT) or magnetic resonance imaging (MRI) should be performed in patients diagnosed with MG to assess for thymoma.

Myasthenia gravis commonly coexists with other autoimmune disorders. Testing for anti-nuclear (ANA) antibodies, rheumatoid factor (RF), and baseline thyroid functions are recommended.

How to manage?

  • The mainstay of treatment:
    • Cholinesterase enzyme inhibitors and immunosuppressive agents.
  • If symptoms are resistant to primary treatment modalities or those requiring rapid resolution of symptoms (myasthenic crisis),
    • Plasmapheresis or
    • Intravenous immunoglobulins
  • International Consensus Guidance for Management of Myasthenia Gravis: 2020
    1. Rituximab should be considered as an early therapeutic option in patients with MuSK-Ab+ MG who have an unsatisfactory response to initial immunotherapy.
    2. The efficacy of RTX in refractory AChR-Ab+ MG is uncertain. It is an option if patients fail or do not tolerate other IS agents.
    3. Eculizumab should be considered in the treatment of severe, refractory, AChR-Ab+ generalized MG.
    4. Methotrexate: Although evidence from RCTs is lacking, oral MTX may be considered as a steroid-sparing agent in patients with generalized MG who have not tolerated or responded to steroid-sparing agents that are better supported by RCT data.
    5. Other important Recommendations:
      • Ophthalmoparesis or ptosis in ocular MG that is not responding to anticholinesterase agents should be treated with immunosuppressant agents if symptoms are functionally limiting or troublesome to the patient.
      • Corticosteroids should be used as the initial IS agent in ocular MG. Steroid-sparing IS agents may be needed when corticosteroids alone are ineffective, contraindicated, or not tolerated.
      • Data from a single small RCT suggest that low-dose corticosteroids may be effective for ocular MG and may avoid side effects associated with high-dose corticosteroids.
      • AChR-Ab+ patients with ocular MG who do not respond adequately to acetylcholinesterases and who either prefer not to take IS therapy or have contraindications to or are refractory to IS agents may be offered thymectomy.

CME INDIA Tail Piece

Rare Case of Autoimmune Target of Muscle and Heart. Was it TIA?

Courtesy: International Consensus Guidance for Management of Myasthenia Gravis: 2020(6)

References:

  1. Li L,Xiong WC,Mei L, Neuromuscular Junction Formation, Aging, and Disorders. Annual review of physiology. 2018 Feb 10;     [PubMed PMID: 29195055]
  2. Statland JM,Ciafaloni E, Myasthenia gravis: Five new things. Neurology. Clinical practice. 2013 Apr;     [PubMed PMID: 23914322]
  3. Murthy JMK, Myasthenia Gravis: Do the Subtypes Matter? Annals of Indian Academy of Neurology. 2020 Jan-Feb;     [PubMed PMID: 32055109]
  4. Wang L,Zhang Y,He M, Clinical predictors for the prognosis of myasthenia gravis. BMC neurology. 2017 Apr 19;     [PubMed PMID: 28420327]
  5. Narayanaswami P, Sanders DB, Wolfe G, Benatar M, Cea G, Evoli A, Gilhus NE, Illa I, Kuntz NL, Massey J, Melms A, Murai H, Nicolle M, Palace J, Richman D, Verschuuren J. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. 2021 Jan 19;96(3):114-122. doi: 10.1212/WNL.0000000000011124. Epub 2020 Nov 3. PMID: 33144515; PMCID: PMC7884987.
  6. Kon, Tomoya & Mori, Fumiaki & Tanji, Kunikazu & Miki, Yasuo & Kimura, Tamaki & Wakabayashi, Koichi. (2012). Giant cell polymyositis and myocarditis associated with myasthenia gravis and hymoma. Neuropathology : official journal of the Japanese Society of Neuropathology. 33. 10.1111/j.1440-1789.2012.01345.x.
  7. Suzuki S, Utsugisawa K, Yoshikawa H, et al. Autoimmune Targets of Heart and Skeletal Muscles in Myasthenia Gravis. Arch Neurol. 2009;66(11):1334–1338. doi:10.1001/archneurol.2009.229


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