Draft 3@AJND

Optimizing clinical complexity in neurodegenerative disorders using medical cognition tools 

Case Presentation:

Case 1: A 51 years old farmer, a chronic tobacco consumer, presented with swelling of the left foot for 3 years, loss of all sensations in the left foot for 3 years, and a painless ulcer

in the sole of the left foot for 11 months.
He reported having an injury of the left foot 25 years ago, that led to swelling of the left foot, associated with pain, that subsided on taking medication.
He reported having another injury of the left foot 3 years ago. The X-ray of the left foot revealed a fracture near the base of the 5th metatarsal. Due to financial constraints, he could not undergo surgery and continued to take medication for the pain and swelling for 9 months and discontinued as the swelling did not subside. The patient reported walking with a limp.
The patient also reported of development of a tingling sensation in his left foot followed by progressive loss of sensation, and inability to wear his left slipper, as it would slip forward. He complains of difficulty while walking and an inability to do his daily work. The patient initially did not notice the ulcer in the sole of the left foot, due to loss of all sensations. He has no history of any skin changes, fever, or hypopigmented patches.
On examination, the patient was conscious, coherent, and oriented to time, place, and person. CNS examination revealed normal cranial nerve function and no focal neurological defects. Steppage gait was present. Examination of the movement at the left ankle revealed the absence of dorsiflexion and eversion and presence of plantar flexion and inversion and a loss of toe extension. The knee jerk reflex and ankle jerk reflex were present in the left lower limb and the plantar reflex was absent.
On sensory examination, the fine touch, crude touch, pain, temperature, and vibration sensations were absent below the ankle joint. A palpable and thickened common peroneal nerve was present in the lateral aspect of the knee joint of the left leg.

Investigations, MRI of the left leg revealed a long segmental fusiform swelling of the tibial nerve with cystic spaces involving the nerve in the distal 1/3rd of the leg, tarsal tunnel, and proximal part of the hindfoot with a maximum thickness of 12 mm. A similar lesion is seen in the long segment of the common peroneal nerve at the level of the knee joint associated with fatty atrophy of the extensor compartment muscles of the leg in the mid and distal 1/3rd of the leg. Suggestive of intraneural ganglion of the tibial nerve, Hamartoma of the tibial nerve, or, Nerve sheath tumor of the tibial nerve.

HRUS examination of the left leg revealed a long segmental focal fusiform enlargement of the distal sciatic nerve just proximal to the bifurcation in the popliteal fossa 10 mm maximum in diameter. Enlargement extends into the common peroneal nerve for about 6 cm and also involves a proximal few 2 cm of the tibial nerve. The extended nerve shows hyperechoic echotexture. Suggestive of a Nerve sheath tumor.

Motor nerve conduction studies revealed no response in the left tibial nerve and left peroneal nerve recorded at the Adductor hallucis and Extensor digitorum brevis muscles respectively. Sensory nerve conduction studies revealed no response in the left superficial peroneal nerve and left sural nerve below the level of the ankle.

Slit skin smear/ skin biopsy was negative for acid-fast bacilli. Bacterial culture of ulcer exudate revealed the presence of Klebsiella species. Blood work revealed the presence of hemoglobin of 9.9 gm% (moderate anemia), with microcytic hypochromic anemia.

The diagnosis was left lower limb mononeuropathy with thickened nerves with etiology under clinical evaluation. Treatment that was given included Gabapentin tablets 100 mg, Multivitamin supplements and amitriptyline tablets 25mg.

Case 2: A 47-year-old male presented with a history of uncontrolled movements in his fingers and toes for the past 3-4 years, slurring of speech for the past 3 years, difficulty in swallowing for the past 2 years, and urinary incontinence. He also complained of water leaking out of his nose while drinking. The movements initially occurred 1-2 times a day, but the frequency and severity have progressively increased to 5-6 times a day, even during his sleep. The patient reported no weakness or loss of grip during the movements, and there were no identifiable triggers or relieving factors.

The patient had no past medical history of DM, hypertension, asthma, or epilepsy. The patient had a personal history of occasional alcohol consumption and smoking 1-2 cigarettes per day.

The patient reported that his mother, sister, and aunt suffered from similar symptoms, with all of them becoming immobilized towards the end. His aunt passed away at an early age due to these symptoms.

On examination, the patient exhibited high-amplitude, low-frequency tremors with no identifiable triggers or relieving factors. Cerebellar signs were present, but titubation and gait/stance ataxia were absent. Nystagmus and dysarthria were not observed, and hypotonia was not present. The patient demonstrated a positive rebound phenomenon, and slight hypometria was observed during the finger- nose test. The patient was unable to perform the knee heel test. Dysdiadokokinesia was not observed. The patient was instructed to say "ma," "ba," "pa," "ta," "da," "la," "ka," and "gha," and was able to repeat them without difficulty. Weak raising of the palate was noted when the patient was instructed to say "AAA." The patient scored 26 on the MMSE.

Case 3: Dr Bhagyajyoti

Case 4: Dr Bhagyajyoti
Case 5: A 59-year-old female , company employee, presented with bilateral upper and lower limb

weakness for 6 months.

The weakness initially began in her left lower limb, it was insidious in onset and progressive in nature. She experienced frequent falls while carrying out her daily activities and experienced multiple injuries on her lower limbs.

Gradually, she developed weakness in the left upper limb.
She was able to carry out her daily activities with discomfort for 4 to 5 months, after which the weakness spread bilaterally to her right upper and lower limb.

She was unable to maintain her balance or walk without support and required assistance to bathe or use the washroom. The patient was unable to raise her lower limbs from the bed in supine position and complained of neck pain radiating bilaterally to her upper limbs.

On examination, the bulk and power of the muscles were reduced and deep tendon reflexes were exaggerated bilaterally in both upper and lower limbs.
There were no deficits in her cognition or memory, no dysarthria or loss of sensations, and her bowel and bladder movements were normal.

Her Laboratory investigations revealed raised ESR (25mm/hr) and mild normocytic, normochromic anaemia. Liver function tests, Renal function tests, Thyroid profile and Vitamin D estimations were within normal ranges.

MRI of the cervical spine revealed
- Mild posterior central and bilateral subarticular disc protrusions at C5-C6 levels, indenting the anterior subarachnoid space, spinal cords and bilateral exciting nerve roots.
- Mild Posterior central disc bulge at C3, C4 Level without significant nerve root compression. -Spinal Canal narrowing at C5-C6 and C6 -C7 levels due to disc protrusions and flaval ligament thickening.

EMG study revealed decreased motor unit recruitment with low amplitude polyphasic MUAP and abnormal spontaneous activity–fasciculation potentials.

Nerve conduction velocity study suggested axonopathy and demyelinating early polyneuropathy. In the Motor Conduction Study there was wide and low amplitude CMAP present in bilateral Median, Ulnar, Common Peroneal and Tibial nerves with normal conduction velocities and normal F wave latency.

The Sensory conduction study done on the bilateral median, ulnar and sural nerves revealed normal conduction velocity and normal amplitude SNAP.

Thus, the patient was diagnosed with Amyotrophic Lateral Sclerosis and was started on the tablet riluzole 50 mg twice a day and vitamin E supplementation.

Case 6: A 37-year-old male, born in 1986 in Medak district, presented with insidious onset of

urinary and stool incontinence and erectile dysfunction, which had been gradually progressive since 2017. The patient was born in lower socioeconomic status and achieved normal milestones. He has

the habit of having one glass of beer and one glass toddy in the evening initially, and later increased to two bottles of beer and a quarter of alcohol.

In 2013, the patient was bitten by a snake in his left lower limb while emptying his bladder in the fields. He lost consciousness and was taken to a nearby herbal medicine doctor who gave him herbal medicines. After gaining consciousness in the morning, he used herbal medicines for five months, and his left lower limb swelling subsided gradually. However, after swelling subsided, the patient started noticing numbness and sensation loss in his right leg, but did not get any aid and carried on with his daily activities.

In 2017, the patient had an insidious onset of urinary and stool incontinence, erectile dysfunction, and progressive weakness. Due to affordability issues, he went back to his town and consulted a local MBBS doctor who advised him medications (unknown) for 10 days. The patient had no relief and went for herbal medications, but had no improvement. He stopped going for work outside since then and sits idle at home. The patient gets anger outbursts often when children irritate him. He tried homeopathy medicine for one month, and on the advice of the homeopathy doctor, he stopped consuming alcohol for two months, but because of cravings, he still drinks on Sundays.

The patient sometimes has anxiety and feels generalized weakness. The patient also reported occasional incontinence while passing stools and urine. An MRI lumbar spine was taken, which suggested a neoplastic etiology (ependymoma or astrocytoma).

Case Discussion:

Case 1: DISCUSSION:

Clinical Autopsy:

The patient's history and examination results suggest a genetic condition that affects the cerebellum and basal ganglia, leading to progressive symptoms such as uncontrolled movements, difficulty swallowing, slurred speech, and urinary incontinence.

The patient’s high-amplitude, low-frequency tremors suggest an essential tremor, which is common in the older adults (1). However, the relatively young age and family history of the patient pull us to a differential of a hereditary neurodegenerative disorder like Huntington’s Disease or Spinocerebellar Ataxia. 

The presence of mild ataxia, positive rebound phenomenon, and slight hypometria during finger-nose test further support the diagnosis of a cerebellar disorder (2). Cerebellar Neurological Signs - StatPearls - NCBI Bookshelf (nih.gov). The weakness in raising the palate when the patient said ‘AAA’ indicates the involvement of bulbar muscles, which can also be seen in many neurodegenerative disorders affecting the basal ganglia. 

Differentials:

The patient's atypical presentation and autosomal-dominant pattern prompted us to consider other differentials that follow a similar pattern, such as Huntington’s disease-like 1, Huntington’s disease-like 2, spinocerebellar ataxia (SCA) type 2, SCA type 17 (3). Of these, HDL2 is the most commonly identified differential, characterized by the presence of acanthocytes (4). SCA can be easily differentiated from HD by MRI findings that show pons and medullary atrophy, in contrast to the caudate and putamen atrophy seen in HD (3).

Based on the patient’s family history and clinical examination findings, a diagnosis of spinocerebellar ataxia (SCA) was considered. SCA is an autosomal-dominant, progressive, neurodegenerative disorder that mainly affects the cerebellum. It can involve other areas such as basal ganglia, and peripheral nerves, which accounts for the patient’s symptoms of bladder incontinence. Stress induced urinary incontinence in patients with spinocerebellar degeneration | Journal of Neurology, Neurosurgery & Psychiatry (bmj.com)

A genetic analysis was done after taking the patient’s consent. The patient’s EDTA blood sample was tested for SCA1, SCA17, and HD. The results came back positive for Huntington’s Disease, which showed that CAG repeats on one of the alleles at the HD locus fell beyond the normal range.

Huntington’s disease (HD) is another progressive neurodegenerative disorder with an autosomal dominant pattern of inheritance. It arises due to a CAG trinucleotide expansion mutation in the huntingtin protein, leading to neuropathological changes in the caudate and putamen regions. The disorder manifests with a spectrum of symptoms, including chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties. (1)

Although chorea is the most common feature in HD, its absence is not unusual, and most patients present with a variable combination of chorea, dystonia, tics, and akinetic-rigid syndrome (2). In the present case, we report the autosomal-dominant hereditary nature of the disease, along with high-amplitude and low-frequency tremors in the hands, and few cerebellar signs. 

Given the atypical presentation in this case, an accurate clinical diagnosis of HD would not have been possible. 

Ref:

(1)  Essential tremor—the most common movement disorder in older people | Age and Ageing | Oxford Academic (oup.com).  

(2) Huntington's disease - ScienceDirect

(3)    Louis ED, Lee P, Quinn L, Marder K. Dystonia in Huntington’s disease: prevalence and clinical characteristics. Mov. Disord. 14, 95–101 (1999).

(3)    Differential diagnosis of Huntington's disease: what the clinician should know - PubMed (nih.gov)

(4)    Wild EJ, Mudanohwo EE, Sweeney MG et al. Huntington’s disease phenocopies are clinically and genetically heterogeneous. Mov. Disord. 23, 716–720 (2008).

Case 2: Huntington’s disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant pattern of inheritance. It arises due to a CAG trinucleotide expansion mutation in

the huntingtin protein, leading to neuropathological changes in the caudate and putamen regions. The disorder manifests with a spectrum of symptoms, including chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties. (1)

In the present case, we report the autosomal-dominant hereditary nature of the disease, along with high-amplitude and low-frequency tremors in the hands, and few cerebellar signs. There was no evidence of cognitive decline. Although chorea is the most common feature in HD, its absence is not unusual, and most patients present with a variable combination of chorea, dystonia, tics, and akinetic- rigid syndrome (2)

Given the atypical presentation in this case, an accurate clinical diagnosis of HD would not have been possible. The patient's atypical presentation and autosomal-dominant pattern prompted us to consider other differentials that follow a similar pattern, such as Huntington’s disease-like 1, Huntington’s disease-like 2, spinocerebellar ataxia (SCA) type 2, SCA type 17 (3). Of these, HDL2 is the most commonly identified differential, characterized by the presence of acanthocytes (4). SCA can be easily differentiated from HD by MRI findings that show pons and medullary atrophy, in contrast to the caudate and putamen atrophy seen in HD (3).

A definitive diagnosis of HD was made only after genetic testing was performed, which showed that CAG repeats on one of the alleles at the HD locus fell beyond the normal range.

(1) Huntington'sdisease-ScienceDirect
(2) LouisED,LeeP,QuinnL,MarderK.DystoniainHuntington’sdisease:prevalenceand

clinical characteristics. Mov. Disord. 14, 95–101 (1999).
(3) DifferentialdiagnosisofHuntington'sdisease:whattheclinicianshouldknow-PubMed

(nih.gov)

(4) WildEJ,MudanohwoEE,SweeneyMGetal.Huntington’sdiseasephenocopiesare clinically and genetically heterogeneous. Mov. Disord. 23, 716–720 (2008).

Case 3: Dr Bhagyajyoti 

Case 4: Dr Bhagyajyoti

Case 5: A middle-aged woman with amyotrophic lateral sclerosis.
This case depicts the clinical proregression of the disease, motor manifestations and the transition from independent movement to functional limitation in a patient with ALS.
The patient was diagnosed with Amyotrophic Lateral Sclerosis, which is also known as “Lou Gehrig’s disease” [1]. It is a fatal neurodegenerative disorder of upper and lower motor neurons characterised by focal onset muscle weakness and rapid disease progression.[2]

Incidence rates of ALS all over the world range between 0.6 to 3.8 per 100000 person years

[3], while in India the frequency of new cases is 5 in 10000[4].

Even though, ALS is a comparatively rare disease, the mortality rates are high.

Approximately 50% of people diagnosed with ALS live at least three or more years after

diagnosis. About 25% live five years or more and up to 10% live more than 10 years [5].

Hence it is the need of the hour to develop, better therapeutics and rehabilitation

treatments.

According to modelling studies, ALS involves interactions between molecular and genetic factors, which lead to a reduced uptake of glutamate (due to dysfunction of excitatory amino acid transporter 2).
Mutations

Learning Outcomes

Characteristic signs

in the superoxide dismuates-1 (SOD-1) gene causing accumulation of intracellular

aggregates and defective axonal transport. [2]

There also is activation of microglia, which results in secretion of proinflammatory cytokines

and subsequent neurotoxicity. [2]

Death of the peripheral motor neurons in the spinal cord and brainstem leads to

denervation and atrophy of corresponding muscle fibres and the loss of fibres in the lateral

columns, the resulting fibrillary gliosis imparts a particular firmness. [6]

ALS typically presents with progressive muscle weakness having a focal onset, associated

with muscle atrophy, fasciculations, muscle cramps, slowness of movements and muscle

stiffness.

In Spinal ALS (seen in two thirds of the patients) the presentation involves unilateral distal

muscle weakness and atrophy of upper or lower limbs. While in Bulbar ALS (seen in one

third of patients) the presentation involves dysarthria or dysphagia. In one third of the

patients, there is presence of exaggerated emotions which is referred to as the

pseudobulbar effect.

On clinical examination, Signs of

Lower Motor Neuron involvement includes muscle weakness, atrophy, fasciculations and

reduced muscle tone, while Signs of UMN include hyperreflexia, increased muscle tone and

slowness of movements. [7]

IN OUR PATIENT

The patient presented with Spinal ALS (as there was absence of dysphagia, dysarthria and

exaggerated emotions).

The disease progression and transition independent movement to dependence for

movement, is depicted in figure 1.

Signs of lower motor neuron involvement included – muscle weakness, atrophy and reduced

muscle tone, while signs of upper motor neuron involvement included – hyperreflexia.

Investigations

MRI of the cervical spine

MRI of the cervical spine is usually done to exclude ALS Mimic syndromes which are a

heterogeneous group of conditions whose presentation and clinical features may resemble

those of ALS at the beginning.[9]

In Autopsies conducted in patients with ALS, 47 per cent individuals depict degeneration of

the corticospinal tract, but the demonstrations of these abnormalities are limited on

conventional MRI [11].

In a study aimed at investigating spinal cord conditions of ALS patients, revealed a higher incidence of cervical cord compression with 53.2 per cent patients depicting cervical cord compression and 38.3 per cent of ALS patients with cervical spondylosis [10].
The Spinal cord in our patient was normal in thickness and revealed normal signal intensity, while there was narrowing of the cervical canal at C5-C6 levels and C6-C7 levels with indentations at anterior subarachnoid space, spinal cords and bilateral exciting nerve roots at C5 C6 Levels due to mild subarticular disc protrusions.

ESR Finding

In patients with ALS, there is evidence of increased levels of C reactive protein and Erythrocyte sedimentation rate as compared to controls [8]. In our patient, there was increased ESR – 25 mm/hr.

Diagnostic and treatment modalities

According to the El Escorial revised criteria [14], the patient was diagnosed with ALS .The patient was started on Tablet Rilozule 50 mg twice a day [13]with vitamin E supplementation.

Learning outcomes

The following consultation occurred as a telecommunication, a PaJR group was created where in a discussion regarding the problems faced by the patient were understood with an aim to find

answers to the patient’s questions. In this case the patient wanted a second opinion in terms of the treatment modalities for the diagnosis. After Discussion about the disease and how the treatment is limited to physical rehabilitation as drugs do not offer a through cure, the patient was less motivated to follow up which acted as a barrier in communication. SWOT analysis of this approach is as follows-

Strength: The patient had a means of communication which was present at all times, with multiple doctors ready to provide opinions – For instance, rehabilitation facilities were explained to the patient in the PaJR group. This approach allows the best possible outcome of the patient without having to visit multiple doctors. There was a systemic medical record formed which would be helpful to the patient in the future, including the patient’s medical history, investigations, examinations at one place making it easily accessible for medical professional treating this patient in the future.

Weakness: Lack of face-to-face consultation further lacking human touch is a major drawback as it would not form an ideal doctor patient relationship. The news to the patient would be communicated over the phone, making it difficult to understand the patient’s reaction. There was a loss to follow up in this patient reasons of which include

• -  Patient factors – lack of motivation (due to the fatal prognosis of the condition), lack of understanding of the motive of the platform, hesitancy to explain problems faced to multiple doctor at once.

• -  Physician Factors – Inability to keep a tally due to excessive number of patients

Opportunities: this approach allowed an open discussion of the rehabilitative treatment for the patient.

Threat: lack of conversation

References

1. Brotman RG, Moreno-Escobar MC, Joseph J, Pawar G. Amyotrophic Lateral Sclerosis. StatPearls Publishing; 2022.

2. van den Bos MAJ, Geevasinga N, Higashihara M, Menon P, Vucic S. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci [Internet]. 2019 [cited 2023 Apr 24];20(11):2818. Available from: https://www.mdpi.com/1422-0067/20/11/2818

3. Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature: An update of recent literature. Curr Opin Neurol [Internet]. 2019 [cited 2023 Apr 24];32(5):771–6. Available from: http://dx.doi.org/10.1097/wco.0000000000000730

4. als - Rare Diseases India [Internet]. Rarediseasesindia.org. [cited 2023 Apr 24]. Available from: http://www.rarediseasesindia.org/als

5. How is ALS Diagnosed and Treated? [Internet]. Hospital for Special Surgery. [cited 2023 Apr 24]. Available from:

   https://www.hss.edu/condition-list_amyotrophic-lateral-sclerosis.asp

6. Brown RH Jr. Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. In: Harrison’s Principles of Internal Medicine. Mc Graw Hill Education; p. 3141–8.

7. Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol [Internet]. 2020 [cited 2023 Apr 24];27(10):1918–29. Available from: http://dx.doi.org/10.1111/ene.14393

8. McCombe PA, Lee JD, Woodruff TM, Henderson RD. The peripheral immune system and amyotrophic lateral sclerosis. Front Neurol [Internet]. 2020 [cited 2023 Apr 24];11:279. Available from: https://www.frontiersin.org/articles/10.3389/fneur.2020.00279/full

9. Ghasemi M. Amyotrophic lateral sclerosis mimic syndromes. Iran J Neurol. 2016;15(2):85–91.

10. MatsuzonoK,SuzukiM,MiuraK,OzawaT,MashikoT,KoideR,etal.Higherincidenceofcervicalspinalcordcompressionin amyotrophic lateral sclerosis: a single-institute cohort study. Neurol Sci [Internet]. 2022 [cited 2023 Apr 24];43(2):1079–86. Available from: https://pubmed.ncbi.nlm.nih.gov/34287724/

11. RochaAJda,MaiaJúniorACM.Ismagneticresonanceimagingaplausiblebiomarkerforuppermotorneurondegenerationin amyotrophic lateral sclerosis/primary lateral sclerosis or merely a useful paraclinical tool to exclude mimic syndromes? A critical review of imaging applicability in clinical routine. Arq Neuropsiquiatr [Internet]. 2012 [cited 2023 Apr 24];70(7):532–9. Available from: https://www.scielo.br/j/anp/a/VT7b4zZPdVk6gfmrTrQ4pnQ/?lang=en

12. JoyceNC,CarterGT.Electrodiagnosisinpersonswithamyotrophiclateralsclerosis.PMR[Internet].2013[cited2023Apr24];5(5 Suppl):S89-95. Available from: http://dx.doi.org/10.1016/j.pmrj.2013.03.020

13. ChenJJ.Overviewofcurrentandemergingtherapiesforamyotrophiclateralsclerosis[Internet].AJMC.2020[cited2023Apr24]. Available from: https://www.ajmc.com/view/overview-of-current-and-emerging-therapies-for-amyotrophic-lateral-sclerosis

14. BrooksBR,MillerRG,SwashM,MunsatTL,WorldFederationofNeurologyResearchGrouponMotorNeuronDiseases.ElEscorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord [Internet]. 2000;1(5):293–9. Available from: http://dx.doi.org/10.1080/146608200300079536 

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Case 6: Dr Sanjana 

Case 7: Dr Riddhi

Case 8: Dr Amili

Sub-heading:

Subheading:

Conclusion: