The Curious Cases of Paraparesis - Case 1

Hello! I'm Sakshi Chittimaneni (Roll No.145), a 4th year medical student.

I've been given these three cases' data here :
https://medicinedepartment.blogspot.com/2020/05/case-based-online-learning-assignment.html?m=1
to solve in an attempt to understand the topic of paraparesis.

CASE 1 :

The details to the patient's entire clinical history, examination findings and investigations can be found here
https://hitesh116.blogspot.com/2020/05/12may-2020-elog-medicine-intern.html?m=1

"AN 18-YEAR-OLD MALE WITH WEAKNESS OF BOTH LOWER LIMBS SINCE 20 DAYS"

After having read and comprehended the data, I have created a problem list in order of the patient's perceived priority following which I have discussed the root causes of these problems :

1. Progressive weakness in both lower limbs of insidious onset since 20 days (SUBACUTE), which began 2 years ago in the proximal region and gradually progressed to the distal region.
2. Difficulty in squatting and getting up from squatting position and climbing stairs              (PROXIMAL LOWER LIMB INVOLVEMENT)
3. Difficulty in wearing and holding chappal (DISTAL LOWER LIMB INVOLVEMENT)
4. No difficulty in combing hair, weight lifting (NO PROXIMAL UPPER LIMB                  INVOLVEMENT)
5. No difficulty in eating, writing , shaving (NO DISTAL UPPER LIMB INVOLEMENT)
6. Slight edema of the lower limbs which is of non-pitting type ( CARDIOMYOPATHY)
7. No symptoms of sensory involvement (GANGLIONOPATHY AND PERIPHERAL        NEUROPATHY ARE RULED OUT)
8. No history of Pain along the nerve root (RADICULOPATHY ALONG SPINAL NERVE  ROOT AND PLEXOPATHY ARE RULED OUT)
9. No history of Fatiguability, Pharyngeal muscle problems (NMJ LESIONS ARE RULED OUT)

Other significant findings on examination are:

• On Examination of the Nervous system,

       Higher mental functions, Sensory system and Cranial nerve functions are normal.
       Motor system: 

       Tone - normal

       Power - 4/5 in both the limbs i.e movement against moderate resistance. 

       Reflexes - absent in both the lower limbs. 

      (LOWER MOTOR NEURON LESION)

• On Examination of the Cardiovascular system,

       Inspection - Normal
       Palpation-

         - Apex heart beat felt downwards and outwards the 5th left intercostal space                                    (DILATED  CARDIOMYOPATHY) 

         - Palpable lift felt 

         - Palpable thrill in the neck (HYPERDYNAMIC  CIRCULATION) 

           Auscultation-

         - S1 and S2 are heard

         - S3 is added

         - Wide fixed split appears to be heard

 (Edit : Wide Split S2 appears to be heard NOT a Fixed Split S2) - Kindly refer to the comments section of the blog for a more detailed discussion about this. 

CAUSES OF THE PROBLEMS :

• Anatomical location of the root cause -

It appears to be an LMN Lesion (as discussed above - Hyporeflexia,Flaccidity, No upper limb involvement, etc)

1. Anterior Horn Cell - Ruled out (Not assymetrical, no wasting, no fasciculations)
2. Dorsal Root Ganglion - Ruled out (No sensory involvement)
3. Spinal Nerve Root - Ruled out (No root pain along distribution of nerve)
4. Plexus - Ruled out
5. Peripheral nerve - Ruled out (No sensory involvement and no distal to proximal evolution hence Pure Motor Neuropathy, although rare, is also ruled out)
6. Neuromuscular Junction - Ruled out (No fatigability, pharyngeal muscle problems)
7. Muscle - It appears to be a muscle problem a.k.a MYOPATHY

• It is purely motor weakness
• Completely symmetrical
• Proximal > Distal, predominantly lower limb
• No sensory loss
• ANS is normal

• Physiological functional disability - 

          Types of Myopathy:

• Intermittent weakness - Ruled out (No previous history of similar weakness)

                - Myoglobinuria -> Rhabdomyolysis 

                - No Myoglobinuria ->Channelopathies, Myasthenia Gravis

• Persistent weakness 

                - Inherited - It appears to be an Inherited defect.

                - Acquired -> 

• Inflammatory - Ruled out (No muscle pain or stiffness. No cutaneous            manifestations as seen in Polymyositis, Dermatomyositis)  
• Endocrine - Ruled out (Thyroid Function tests are normal which rules        out Hoffman syndrome in Hypothyroidism and Hyperthyroidism Induced Myopathy)
• Mitochondrial - Ruled out (Red Ragged Fibers absent on Muscle Biopsy)
• Drugs - Ruled out (No intake of drugs causing myopathies like                        Glucocorticoids)

Inherited Myopathies and Muscular Dystrophies:

           DIFFERENTIAL DIAGNOSES -

1. Becker's Muscular Dystrophy - MOST LIKELY
2. Duchenne Muscular Dystrophy (DMD) Age of onset is between 3 - 5 years
3. Limb Girdle Muscular Dystrophy
4. Emery Dreifuss syndrome 
5. Myotonic Dystrophy

• Biochemical abnormalities that could be a root cause at a molecular level -

        An increased CK level should lead us to suspect a Dystrophinopathy.

       DIAGNOSIS OF A DYSTROPHINOPATHY

• Molecular genetic testing can confirm a diagnosis of a dystrophinopathy and performing a muscle biopsy will not be required.
• Identification of a disease-causing mutation of the DMD gene establishes the diagnosis.

      Techniques - The following methods are available for the molecular genetic analysis of the DMD gene

●Analysis for deletions/duplications using Multiplex ligation-dependent probe amplification (MLPA), Multiplex PCR, Florescence in situ hybridization (FISH), Long-range PCR, Chromosomal microarray (CMA).

●Mutation scanning and sequence analysis to detect point mutations

• Muscle biopsy was once important for the diagnosis of DMD and related disorders but is seldom needed now, since almost all patients are diagnosed with genetic testing.
• A Western blot assay of dystrophin can be used to predict the severity of the disease.
• Electromyography reveals myopathic  changes consisting of small polyphasic potentials. However, it is never used in the diagnosis of DMD and BMD.

Basil T. Darras, (2020). Duchenne and Becker Muscular Dystrophy: Clinical features and diagnosis. In J.F.Dashe (Ed), UpToDate. Retrieved April 2020 from, https://www.uptodate.com/contents/duchenne-and-becker-muscular-dystrophy-clinical-features-and-diagnosis

     

• Pathology that could reflect the root cause at a cellular level -

        BECKER'S MUSCULAR DYSTROPHY 

• It is an X- Linked Recessive Disorder.
• Due to Dystrophin gene mutation
• Variable disease onset (5 -60 years)
• No mental retardation
• No contractures
• Cardiomyopathy is commonly seen.

TREATMENT PLAN :

Here are some solutions to tackle these root causes from upstream (soil from which the roots begin) or downstream (to treating the stem and branches aka palliation) in terms of pharmacological and non pharmacological, both in historical terms (past dominant treatments for the same cause and it's current evolution) as well as recent advances (ongoing trials and innovative approaches) :

1) Solution to tackle the Upstream - 

    EUGENICS in Muscular Dystrophy

• Patient: Diagnosed cases of DMD
• Indicator: Genetic Counseling, Promotion of Euthanasia
• Comparision: The first group comprises the older patients concerning their progressive respiratory insufficiency, whilst systematically requesting adapted ventilation assistance. The second group comprises second generation patients, who benefited from procedures, but for whom the completeness of treatment was not achieved.
• Outcome: "Concerning muscular dystrophy, confusion is inevitable, both in the social incidence, in doubtful intentions, and in a conditioning of consent, despite numerous protections which have already been proposed (genetic counseling, ethical committees, subsequent legislations ). If an urgent Legislation has to intervene, it will not be that claimed now concerning euthanasia, but that allowing the numerous contradictions harming or damaging the priority fight against illness to be clarified."
• Time/ Duration of study : 21.77 years (approximately)
• Type of study : Observational open label study

Y.Rideau & F. Rideau, (2007). Muscular Dystrophy, incurability, eugenics.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949327/

2) Solutions to tackle the Downstream (Palliative treatment)

Pharmacological Treatment -

• Glucocorticoids - In DMD, Prednisone and Deflazacort have been proved to be beneficial for improving motor function, strength, delaying the loss of ambulation reducing the risk of scoliosis, and improvement of Pulmonary function.

 Prednisone is dosed at 0.75 mg/kg per day for the treatment of DMD.

Deflazacort is dosed at 0.9 mg/kg per day.

Novel Therapies-

• Eteplirsen
• Golodirsen
• Ataluren
• Gene therapy
• Creatine monohydrate
• Myostatin inactivation
• Cell therapy
• Idebenone

Basil T. Darras, (2020). Duchenne and Becker Muscular Dystrophy: Glucocorticoid and disease-modifying treatment. In J.F.Dashe (Ed), UpToDate. Retrieved April 2020 from,

https://www.uptodate.com/contents/duchenne-and-becker-muscular-dystrophy-glucocorticoid-and-disease-modifying-treatment

Non-Pharmacological Treatment -

Rehabilitation:

• Long-leg braces for maintaining standing and/or walking 
• Power stand-up motorized wheelchairs provide standing mobility

Health maintainance:

• Nutrition - Obesity and Malnutrition should be controlled by promoting a healthy diet with adequate calories, micronutrients, protein and fluid, especially Calcium and Vitamin D.
• Mental health - Routine assessment of the mental health of the patient and family at every clinic visit and referrals to a psychiatrist or psychologist if required
• Educational and vocational support 

Basil T. Darras, (2018). Duchenne and Becker Muscular Dystrophy: Management and prognosis. In J.F.Dashe (Ed), UpToDate. Retrieved April 2020 from,

"Duchenne and Becker muscular dystrophy: Management and prognosis"

https://www.uptodate.com/contents/duchenne-and-becker-muscular-dystrophy-management-and-prognosis


Additional References:

1. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
2. Marrow Videos and Lecture Notes, E.4. Bengaluru: Neuroglia Health Pvt. Ltd; 2020.