Lathyrism

Definition

• Adams & Victor's Principles of Neurology, 12th Ed.
• Bradley & Daroff's Neurology in Clinical Practice

Historical Background

Epidemiology

• Endemic regions: India (Madhya Pradesh - Rewa and Satna districts had 25,000 and 32,000 cases respectively; also UP, Bihar, Odisha, Maharashtra, West Bengal, Rajasthan, Assam, Gujarat), Bangladesh, Ethiopia, China, Romania, Spain, Algeria, North Africa.
• Trigger: Outbreaks occur during famine and drought, when L. sativus (cheap, hardy, drought-resistant) becomes the dietary staple.
• At-risk group: Mainly young men aged 15-45 years; a higher incidence has been noted in boys aged 10-14 in Ethiopian epidemics.
• Dose threshold: Diets containing over 30% of this dhal, taken over 2-6 months, result in neurolathyrism.
• Park's Textbook of Preventive and Social Medicine

The Pulse

Toxin: BOAA

• A free, water-soluble amino acid found in seed cotyledons (approximately 1%)
• Acts as an AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) glutamate receptor agonist - this is the key excitotoxic mechanism
• Stimulation of AMPA receptors increases intracellular reactive oxygen species (ROS) and impairs mitochondrial oxidative phosphorylation
• There is a blood-brain barrier to the toxin; large amounts must be ingested over months to overcome it
• Water-soluble property is exploited for detoxification (soaking in hot water)

• Betz cells of the motor cortex (especially those subserving lower-extremity function)
• The longest corresponding pyramidal (corticospinal) tracts
• Loss of ascending and descending tracts - corticospinal and direct spinocerebellar tracts
• Loss of myelinated fibers in lateral and posterior columns
• Anterior horn cells are relatively spared (hence an upper motor neuron picture)
• Bradley & Daroff's Neurology in Clinical Practice
• Adams & Victor's Principles of Neurology, 12th Ed.

Clinical Features (Stages)

• Severe, agonizing pain in calf muscles
• Weakness in legs; difficulty sitting and standing
• Spastic paraplegia of lower limbs (bilateral)
• Scissor (crossed) gait, tiptoe walking
• Increased knee jerks, ankle clonus, extensor plantar response (Babinski positive)
• Paresthesias, numbness, formication in legs
• Frequency and urgency of micturition, erectile dysfunction, sphincteric spasms
• Coarse tremor and involuntary movements of upper extremities (occasionally)
• No sensory loss, no loss of consciousness (classically)
• No atrophy initially, no reaction of degeneration, muscle tone maintained

Prevention and Control

(a) Vitamin C prophylaxis

(b) Banning the crop

• India's Prevention of Food Adulteration Act has banned Lathyrus in all forms (whole, split, flour).
• The ban is poorly enforced in endemic states (MP, Bihar, Odisha, Gujarat).
• If unavoidable, khesari dhal should not exceed 25% of total cereals and pulses per day.

(c) Removal of toxin (Detoxification)

1. Steeping method: Soak pulse in hot (boiling) water for 2 hours, drain, wash with clean water, dry in sun. Drawback: some vitamin/mineral loss.
2. Parboiling: Soak in lime water overnight then boil - destroys BOAA and trypsin inhibitors. Suitable for large-scale operations.

(d) Genetic approach

(e) Public education

Treatment

• Exclude L. sativus from the diet (early withdrawal may cause remission in the latent stage)
• Diet rich in Vitamin A, carotene, and other vitamins
• Physiotherapy for muscular and neurological involvement
• Vitamin C supplementation

Comparison with Konzo

• Toxic nutritional UMN diseases
• Affect longest corticospinal tracts and Betz cells
• Occur in famine conditions in developing countries
• Irreversible but non-progressive

Key Exam Points

• Toxin: BOAA (Beta-N-Oxalylamino-L-Alanine) - AMPA receptor agonist
• Mechanism: Excitotoxic; selective UMN / corticospinal tract degeneration
• Clinical: Spastic paraplegia, scissor gait, tiptoe walking - pure UMN, no sensory loss
• Population: Young men, famine conditions, diet >30% L. sativus for >2 months
• Reversible only at latent stage (withdraw the pulse)
• Detoxification: Hot water soaking (BOAA is water-soluble)
• India: Banned under Prevention of Food Adulteration Act
• Local name: Khesari dhal (triangular grey seeds)

Causalgia (CRPS Type II)

Definition and Terminology

• CRPS I = no definable nerve lesion (formerly RSD)
• CRPS II = definable nerve lesion (formerly causalgia)
• Adams & Victor's Principles of Neurology, 12th Ed.
• Bradley & Daroff's Neurology in Clinical Practice
• Rockwood & Green's Fractures in Adults, 10th Ed.

Nerves Commonly Involved

• Median nerve (most common)
• Ulnar nerve
• Sciatic nerve
• Peroneal nerve

Clinical Features

Pain (Cardinal Feature)

• Severe, persistent burning pain - the hallmark
• Located in the hand or foot, most pronounced in the digits, palm, or sole
• Radiates beyond the territory of a single peripheral nerve
• Severity is disproportionate to the initiating injury
• Not limited to the area of injury or a specific nerve distribution

Sensory Abnormalities

• Allodynia - innocuous stimuli (light touch, clothing, drafts of air) cause severe, long-lasting pain
• Hyperalgesia - exaggerated pain to minor stimuli (e.g., safety pin prick)
• Thermal allodynia - even a drop of alcohol or ambient heat/cold intensifies pain
• Even emotional stimuli, noise can worsen the pain
• The patient keeps the extremity protected and immobile, often wrapped in cool, moist cloth

Autonomic/Vasomotor Changes

• Sudomotor changes: excessive sweating (~60% of patients)
• Vasomotor instability: skin alternates between red, blue, purple, or pale within minutes to hours
• Livedo reticularis - reticulated red network pattern on skin
• Temperature asymmetry between limbs (>1°C)
• Early: warm, moist skin; Later: cold, cyanotic limb

Trophic Changes (later)

• Shiny, smooth, sometimes scaly skin devoid of hair
• Abnormal nail growth (increased or decreased)
• Hyperkeratosis
• Osteoporosis of underlying bone (Sudeck's atrophy)
• Muscle atrophy

Motor Dysfunction

• Mild weakness
• Decreased range of motion
• Tremor, dystonia, myoclonus

Edema

• Mild early (may mimic cellulitis)
• Severe late (may require Doppler to exclude DVT)

Three Stages (RSD Classification - Firestein/Kelley Rheumatology)

Pathophysiology

1. Ephaptic transmission (short-circuiting): Abnormal direct electrical connection between efferent sympathetic and somatic afferent pain fibers at the nerve injury site.
2. Adrenergic chemical coupling: Depletion of neurotransmitters at sympathetic adrenergic endings abolishes causalgic pain - suggesting chemical (not electrical) cross-excitation at nerve terminals. Injured nociceptors develop abnormal adrenergic sensitivity and respond to circulating sympathetic neurotransmitters.
3. Central sensitization: Sustained sensory pain bombardment sensitizes central structures. Molecular changes include:
   • NMDA receptor alterations
   • Induction of cyclooxygenase and prostaglandin synthesis
   • Changes in GABAergic inhibition in dorsal horns
4. Neuroinflammation: Elevated CGRP (calcitonin gene-related peptide) drives neurogenic inflammation, edema, vasodilation, and sweating.
5. Immunological mechanisms: Altered HLA expression, substance P, cytokines, and interleukins contribute to edema and pain.
6. Cortical reorganization: Disinhibition of motor cortex; reorganization of primary somatosensory cortex.

• Bradley & Daroff's Neurology in Clinical Practice
• Adams & Victor's Principles of Neurology, 12th Ed.

IASP Diagnostic Criteria (Original)

1. Presence of an initiating noxious event or cause of immobilization (not required - 5-10% have none)
2. Continuing pain, allodynia, or hyperalgesia disproportionate to any known inciting event
3. Evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of pain at some time
4. Diagnosis excluded by other conditions that would otherwise account for the degree of pain and dysfunction

Special Presentations

• Causalgia-dystonia syndrome (Bhatia et al.): A fixed dystonic posture engrafted on a site of causalgic pain. Injury is often trivial or absent; both the causalgia and dystonia can spread to distant sites. Does not respond consistently to treatment; some spontaneous recovery occurs.
• Algodystrophy post-DVT: Causalgia and RSD following deep venous thrombosis in a leg.
• Mimocausalgia: Causalgic pain arising from CNS lesions rather than peripheral nerve injury.

Treatment

Physical/Occupational Therapy

• First-line in early CRPS - movement, desensitization

Pharmacological

Sympathetic Interventions

• Sympathetic nerve block - can reverse the syndrome, especially in Stage 1
• Intravenous regional sympathetic block (Bier block)
• Surgical sympathectomy - Leriche (1916) was the first to demonstrate that sympathectomy could alter the clinical features

Psychological

• Psychological evaluation for patients with CRPS >2 months
• Cognitive behavioral therapy, biofeedback, relaxation therapy, group therapy, self-hypnosis

Neuromodulation

• Spinal cord stimulation for refractory cases

Key Exam Points

• Term coined by Weir Mitchell (1870s); renamed CRPS by IASP in 1994
• CRPS I = no nerve lesion (RSD); CRPS II = nerve lesion present (causalgia)
• Most common nerves: median > ulnar > sciatic > peroneal
• Requires partial nerve injury (not complete)
• Pain is burning, disproportionate, beyond nerve territory, with allodynia and autonomic changes
• Patient keeps limb wrapped in cool moist cloth
• Three stages: acute (warm) → dystrophic (atrophy) → atrophic (irreversible contracture)
• Best pharmacological evidence: bisphosphonates
• Sympathetic block can produce dramatic relief

Jendrassik Manoeuvre

Definition

How It Is Performed

1. The patient flexes the fingers of both hands into a hook-like form
2. The two hands are interlocked at the fingers
3. The patient is asked to pull the hands apart isometrically (as hard as possible, without actually unlocking the fingers)
4. While this sustained effort is maintained, the patellar (knee jerk) or Achilles reflex is elicited by striking the tendon

• Upper limb reflexes (biceps, triceps, brachioradialis) can be reinforced by asking the patient to voluntarily clench their teeth
• The Achilles reflex can also be reinforced by the same finger-hooking technique
• Harrison's Principles of Internal Medicine, 22nd Ed.
• Firestein & Kelley's Textbook of Rheumatology

Mechanism of Action

Normal Stretch Reflex Arc (brief recap)

• Tapping the tendon stretches the muscle spindle (intrafusal fibers)
• This activates Ia afferent fibers (large, fast-conducting) from the spindle
• Ia fibers synapse directly (monosynaptically) on alpha (α) motor neurons in the anterior horn
• Alpha motor neurons activate extrafusal (skeletal) muscle fibers → visible reflex jerk

Role of Gamma Motor Neurons

• Gamma (γ) motor neurons innervate the intrafusal fibers of the muscle spindle
• When γ-motor neuron discharge increases → intrafusal fibers contract → spindle is "loaded" (put under tension)
• A loaded spindle is more sensitive to stretch - it fires more readily and more vigorously when the tendon is tapped
• This amplifies Ia afferent traffic → stronger alpha motor neuron activation → brisker reflex

How the Manoeuvre Works

• The isometric pulling effort of the hands activates afferent impulses from the hand muscles and tendons
• These afferent signals travel to the spinal cord and increase γ-motor neuron discharge to the lower limb muscles
• The spindles become more sensitive (loaded)
• When the tendon is then struck, the reflex arc is amplified - a previously undetectable reflex becomes visible

"Trying to pull the hands apart when the flexed fingers are hooked together facilitates the knee jerk reflex (Jendrassik maneuver), and this may also be due to increase γ-motor neuron discharge initiated by afferent impulses from the hands."

• Ganong's Review of Medical Physiology, 26th Ed.

• Ganong's Review of Medical Physiology, 26th Ed.
• Firestein & Kelley's Textbook of Rheumatology

Clinical Significance

When to Use It

• Any time a reflex appears absent or diminished on initial testing
• Should be routinely attempted before recording a reflex as absent (0)
• Especially important for the patellar and Achilles reflexes, which are most commonly suppressed by voluntary muscle tension or patient anxiety

Interpretation

Grading Scale (Harrison's)

Additional Physiological Notes

• Anxiety independently increases γ-motor neuron discharge, explaining why anxious patients may have hyperactive reflexes
• Unexpected movement also increases γ-motor neuron efferent discharge
• Noxious skin stimulation increases γ-motor neuron activity to ipsilateral flexor spindles while decreasing it to extensors (explains flexor withdrawal patterning)
• The manoeuvre works because of α-γ co-activation: descending excitatory input simultaneously activates both α and γ motor neurons, keeping the spindle sensitive throughout muscle contraction

Key Exam Points

• Named after Erno Jendrassik (Hungarian, 1885)
• Technique: interlock flexed fingers of both hands and pull apart while the knee/ankle jerk is tested
• Mechanism: increases γ-motor neuron discharge → loads muscle spindle → amplifies Ia afferent input → stronger reflex
• Also works via distraction (reduces voluntary cortical suppression)
• Upper limb equivalent: voluntary teeth-clenching
• A reflex absent even with reinforcement = truly absent (lower motor neuron pathology)
• Anxiety → increased γ-motor discharge → hyperreflexia (same underlying mechanism)