Juvenile distal segmental spinal muscular atrophy, also known as Hirayama disease, is a rare condition characterized by slowly progressive asymmetric weakness and atrophy of hand and forearm muscles, typically affecting young males. The pathophysiology is thought to involve flexion-induced compression of the lower cervical spinal cord during neck flexion. MRI with neck flexion shows anterior displacement and flattening of the cervical cord. There is no effective treatment, but symptoms typically stabilize within a few years.

1. Juvenile distal segmental spinal muscular atrophy
Hirayama’s disease
Jo Caekebeke
VNV 2014

2. Casus
• Jonge man °1995, rechts handig, 1m81, 63kg
• Vlotte student, jogging
• Medische voorgeschiedenis: geen bijzonderheden
• Familiale anamnese: geen bijzonderheden
• Anamnese:
• Sinds > 1 jaar traag progressieve last in de rechter hand
• Minder kracht en oa last bij het schrijven…
• Iets beter na het opwarmen van de handen
• Geen pijn noch gevoelsstoornis of krampen
• Geen last in de andere ledematen
• Geen andere neurologische klachten

3. Casus
• Neurologisch onderzoek:
• Helder bewustzijn, hogere cerebrale fie normaal
• Craniale zenuwen: normaal, anamnestisch geen slikstoornis
• Kracht:
• In benen: normaal
• In armen: volgende dia
• Sensibiliteit: voor alle kwaliteiten symmetrisch en normaal
• Reflexen symmetrisch en normaal, VZR: in flexie
• Coördinatie: normaal
• Gangpatroon: normaal

4. Casus: kracht in de armen
Spieren Rechts Links
Kracht Atrofie Kracht Atrofie
Deltoideus & schouder spieren 5 - 5 -
Biceps brachii & brachialis 5 - 5 -
Triceps brachii 5 - 5 -
Brachioradialis 5 - 5 -
Pols & vinger extensoren 5- + 5 -
Pols & vinger flexoren 4 ++ 5 -
Centrale intrinsieke handspieren 4 +++ 5- +-
Duimmuis spieren 4 ++ 5 -
Pinkmuis spieren 4- +++ 5- +-

5. Casus
• Lab
• Hematologie, chemie: normaal
• CRP, CK, TSH: normaal
• Borrelia serologie: negatief
• Anti gangliosides Ab: negatief
• Β hexosaminidase: normaal
• EMG:
• Normale motorische en sensibele geleidingssnelheden
• PSW’s en fibrillaties in distale armspieren
• Geen geleidingsblocks

8. Differential diagnosis: more than weakness ?
• Asymmetric distal weakness but also pain and/or sensory deficit…
• Carpal tunnel syndrome
• Ulnar neuropathy at elbow (or at the wrist)
• Sudeck’s atrophy
• Thoracic outlet syndrome
• Neuralgic amyotrophy (Parsonage -Turner)
• Occasional cases with a near painless onset
• Polyneuropathy
• Mononeuritis multiplex
• Spinal radiculopathy
• Intrinsic and extrinsic cervical myelum pathology

9. Differential diagnosis: progressive focal weakness ?
• Acute poliomyelitis and postpolio progressive muscular atrophy (PPMA)
• Multifocal motor neuropathy (MMN)
• Immune-mediated, anti GM1 Ab (20 – 60%)
• Slowly progressive asymmetrical distal weakness
• Predominant upper limb involvement
• Cramps and fasciculations
• Conduction blocks...
• IVIg therapy
• Hereditary Welander distal myopathy
• AD, predominantly affecting the hands, slow progression
• Sweden & Finland, TIA1 mutation

10. Differential diagnosis: progressive focal weakness ?
• ALS and ALS-like diseases
• Juvenile ALS (JALS): onset of disease before 25 years, typically familial
• UMN & LMN signs, slow disease progression (Stephen Hawking?)
• Flail arm syndrome
• Man-in-the-barrel syndrome or brachial amyotrophic diplegia
• Proximal > distal; symmetric, slow progression
• Kennedy’s disease: spinobulbar muscular atrophy (SBMA)
• X-linked, expansion of CAG repeats in androgen receptor gene
• Proximal > distal LMN signs, gynecomastia, testicular atrophy...
• Lower motor neuron diseases
• LMND: after > 4 years only < 10% continue to show LMN signs only
• Hereditary and sporadic spinal muscular atrophy

11. Differential diagnosis: hereditary HMN / SMA ?
• Proximal HMN or classical hereditary SMA (type IV, adult onset)
• SMN1,2 gene related
• Symmetrical proximal muscular atrophy
• Distal HMN or hereditary distal SMA1
• Clinical and genetic heterogeneity, mostly foot predominance
• Resemble axonal CMT2 syndromes (spinal CMT)
• > 7 subtypes (I – VII); AD, AR, X-linked
• Distal HMN V (AD, BSCL2, GARS… mutation)
• Hand predominance, adolescent onset, asymmetrical
• Cave de novo mutations
1. Rossor A. J Neurol Neurosurg Psychiatry 2012; 83: 6-14

12. Differential diagnosis: sporadic LMN disease1,2,3 ?
• Progressive (spinal) muscular atrophy (PMA)
• Slowly progressive generalized weakness & symmetrical distal weakness
• LMND but after years: ALS may still develop
• Segmental proximal (spinal) muscular atrophy (SPMA)
• Non-generalized asymmetrical proximal weakness
• Segmental distal (spinal) muscular atrophy (SDMA)
• Non-generalized asymmetrical distal weakness
• Progressive segmental distal SMA
• O’Sullivan-McLeod syndrome
• Non-progressive segmental distal SMA
• Hirayama disease
1. Van den Berg-Vos R. Brain 2003; 126:1036-1047
2. Visser J. Archives of neurology 2007; 64: 522-528
3. Van den Berg-Vos R. Archives of neurology 2009; 66: 751-757

13. Hirayama disease1
• 1959: Hirayama disease, (Keizo Hirayama neurologist in Japan)
• 12 pt with predominantly unilateral weakness, atrophy of fingers and hand
• Largest series in Japan, India, Taiwan, Singapore and China
• Nosology:
• Hirayama disease (HD)
• Monomelic amyotrophy (MMA)
• Juvenile muscular atrophy of unilateral upper extremity
• Juvenile muscular atrophy of the distal upper extremity (JMADUE)
• Juvenile asymmetric segmental SMA (JASSMA)
• Segmental distal SMA
• Hirayama flexion myelopathy
1. Hirayama K. Japanese journal of psychiatry and neurology 1959; 61: 2190-2197

14. Clinical features
• Young persons (11 – 25y), mostly in males (89%)
• Often slender sportsman
• Almost all cases are sporadic
• Not linked to SOD1, SMN1, SMN2, BSCL2, GARS, androgen receptor genes
• A few reports of familial Hirayama disease with or without MRI findings1
• Insidious onset of unilateral or asymmetric atrophy of the hand and forearm
• Without precipitant toxic history, infection or trauma
• Nearly all patients report worsening of weakness in cold environment
• Often first notice their disease during winter
1. Atchayaram N. Neurology India 2009; 57: 810-812

15. Clinical features
• Atrophy and weakness in C7 – T1 myotomes
• Brachioradialis muscle is mostly spared (oblique amyotrophy)
• Right side is more often affected, regardless of handedness
• Ulnar territory is more affected than median one
• Unilateral in most patients (72%)
• Asymmetrically bilateral in 25%
• Rarely symmetric in 3%
• May progress to the opposite site

16. Clinical features
• Moderate extension of the fingers produces fine, fast, irregular tremor
• Minipolymyoclonus, contractile fasciculation
• Fasciculations are rare when the hand is at rest
• No sensory impairment
• Occasional hypoesthesia in dorsum of the hand
• No involvement of cranial nerves, lower limbs or pyramidal signs
• Reflexes are within normal range ore reduced in upper limbs
• Sometimes hyperreflexia in lower limbs, babinski sign in very few cases

17. Prognosis
• Initial progressive course, followed by a spontaneous arrest:
• In 70%: within 3 years
• In 90%: within 6 years
• Before the age of 25 years in majority of cases
• After this period of time, the disease neither improves nor worsens
• Some cases do progress but extremely slowly
• O’Sullivan-McLeod syndrome versus Hirayama disease
• Lumpers versus splitters

18. Neurophysiology
• Needle EMG shows chronic denervation in C7, C8, T1 myotomes
• Ulnar territory is more affected than median territory
• Common subclinical involvement of:
• C5, C6 myotomes & “unaffected” upper limb
• EMG of the lower limbs shows a normal pattern
• Sensory neurography is normal
• SSEP: usually normal in neutral and neck flexion
• Sometimes attenuation of responses particularly during neck flexion
• MEP: normal in latency and amplitude
• CMCT between cortex and C8/T1 is sometimes marginally prolonged

19. Routine cervical spine MRI findings
• May show atrophy of the lower cervical cord
• Mild antero-posterior flattering of spinal cord, at C6 vertebral level
• Asymmetrical, corresponding to the more atrophied limb
• Loss of attachment between the posterior dural sac and subjacent lamina
• Most valuable finding for diagnosing Hirayama disease in routine MRI1
• Specificity 100%, sensitivity 70 – 93%2
• No abnormal intrinsic cord signal
1. Chen CJ. Radiology 2004; 231: 39-44
2. Lehman V. Am J Neuroradiol 2013; 34: 451-456

20. Routine cervical spine MRI findings (Sag T2 FRFSE)

21. Hyperflexion cervical spine MRI findings
• If routine MRI and clinical investigations are inconclusive:
• MRI with hyperflexion contrast study is the gold standard
• Full neck flexion induces forward displacement of the dural sac1,2
• Unequivocal finding in the progressive stage (in 87%)
• Dynamic cord compression with remarkable flattering of the spinal cord at C5-7
vertebral level
1. Biondi A. Am j neuroradiol 1989; 10: 263-268
2. Raval M. Indian J Radiol Imaging 2010; 20: 245-249

22. Hyperflexion cervical spine MRI (Sag T1 FS & T2 FRFSE)

23. Hyperflexion cervical spine MRI (Ax T1 Gd+)
C6
C5
T2

24. Hyperflexion cervical spine MRI findings
• Posterior epidural space:
• Crescent-shaped T1 isointense and T2 hyperintense area
• From C4 – T1 (max at C5 – C7)
• Linear or round flow void signals (low signal) in the high signal area
• Passive dilatation of the posterior epidural venous plexus
• Due to negative pressure in the posterior spinal canal
• Compress of anterior venous plexus and increased burden of
posterior venous plexus
• Venous drainage of jugular veins is reduced in neck flexion, which
impedes venous return of the internal venous plexus
• Uniform enhancement on contrast images

25. Hyperflexion cervical spine MRI findings
• Full dynamic MRI signs are observed when disease duration > 18 months1,2
• In older patients who have reached a stable stage
• The dynamic findings are absent
• But atrophy of the lower cervical cord is still present
• The sensitivity and specificity of the MRI findings are not known
• Discrepant findings In healthy controls:
• Neither cord flattering nor epidural high intensity on flexion1
• Versus anterior dural shift in nearly 50%3
1. Hirayama K. Neurology 2000; 54: 1922-1926
2. Hassan K. Biomed research international 2013; 478516
3. Lai V. Eur J Radiol 2011; 80: 724-728

26. MRI findings1,2
1. Hassan K. Biomed research international 2013; 478516
2. Raval M. Indian journal of radiology and imaging 2010; 20: 245-249

27. Hyperflexion cervical spine MRI (Sag T1 & myelography)

28. MRI evaluation in neutral and flexion position
• Localized lower cervical cord atrophy
• Asymmetric cord flattering
• Abnormal cervical curvature
• Loss of attachment between posterior dural sac and subjacent lamina
• Anterior shifting of posterior wall of cervical dural canal
• Enhancing epidural component with flow voids
• Intramedullary signal hyperintensity

29. Pathology1
• First autopsy (1982)
• 38 y, died of lung cancer, Hirayama’s disease for 23 years, (l > r)
• Second autopsy case
• 76 y, Disease onset at age 24, but also cervical spondylosis later in life
• Antero-posterior flattering and asymmetrical ischemic necrotic changes of
anterior horns of the cervical cord at C5 – T1, mostly at C7 – C8
• Circulatory insufficiency ?
• But intra- and extra-medullary vessels were normal
• Spinal cord atrophy in later stages of the disease
1. Hirayama K. J Neurol Neurosurg Psychiatry 1987; 50: 285-290

30. Pathophysiology: hypotheses
1. Chronic progressive degenerative disease of cervical motor neurons (LMND)
• Sporadic and familial cases without MRI abnormalities1,2
2. Flexion myelopathy3
• On neck flexion, a tight dural sac cannot compensate for the increased
lenght of the posterior wall, which causes anterior shifting of the posterior
dural wall and consequent compression of the cord
• Difference in length between extension and flexion from atlas to T1
1.5 cm at the anterior wall and 5 cm at the posterior wall
• Increased intramedullary pressure, resulting in microcirculatory
disturbance in the anterior horn
1. Willeit J. Acta Neurol Scan 2001; 104: 320-322
2. Andreadou E. Neurologist 2009; 15: 156-160
3. Kikuchi S. Intern Med 2002; 41: 746-748

31. Pathophysiology: spinal dura mater
• Spinal dura mater is a slack, loose sheath1
• Attachment to the periosteum in two places:
• At the foramen magnum and the dorsal surfaces of C2-3
• At the coccyx
• Anchored in the vertebral canal by the nerve roots
• Further suspended, cushioned by epidural fat, venous plexus and loose
connective tissue
• With transverse folds compensating for increased length of a neck in fexion
1. Williams P. Gray’s Anatomy 1987: 1086-1092

32. Pathophysiology: tight dural sac1
• A disproportionate growth between vertebral column and the contents of the
spinal cord
• Leading to a tight dural sac and forward displacement of the myelum
• Dispoportionate shortening of the dural sac is perhaps accentuated during
juvenile growth spurt, explaining the preponderance in adolescence
• Different growth rates between males and females probably related to male
preponderance1
• How to explain racial differences ?
• The absence of forward displacement in a later and non-progressive stage of the
disease suggested that the dynamic compression had pathogenic significance
1. Kikuchi S. Clin Neurol (Tokyo) 1987; 27: 412-419

33. Treatment based on “flexion myelopathy”
• Early recognition1:
• Benign, non-progressive disorder
1. Hard cervical collar therapy, no RCT
• Early therapy may minimize the functional disability2
• For 3 – 4 years, during the progressive stage ?
2. Surgery, case based
• Cervical decompression and/or fusion, duraplasty3 may be an option ?
3. Muscle strengthening exercises and training in hand-coordination
1. Hirayama K. Brain nerve 2008; 60: 17-29
2. Tokumaru Y. Clin Neurol (Tokyo) 1992; 32: 1102-1106
3. Arrese I. Neurocirugia 2009; 20: 555-558

34. Domo Arigato Gozaimasu
The best test of a physician’s suitability for
the specialized practice of neurology is not
his ability to memorize improbable
syndromes but whether he can continue to
support a case of motor neuron disease, and
keep the patient, his relatives and himself in
a reasonable cheerful frame of mind. Matthews WB