Gordon et al 1 APPENDIX e-1

Clinically Pure PLS

A 40 year-old man first noted difficulty getting out of a bathtub and rising from a kneeling position due to stiffness in 1970. He continued to walk to work each day until about 1990 when he began to have more difficulty with his gait. A neurologist noted hyperreflexia including up-going toes in 1993, but MRI of the brain, and cervical and thoracic spine were unremarkable. Laboratory studies including tests for available HSP genes, CBC, chemistries, RPR, protein electrophoresis, ANA, rheumatoid factor, Lyme serology and CSF analysis were normal or negative.

In 1996 he received a course of IVIG which did not result in improvement, and he underwent a prostate procedure which led to some urinary incontinence. He stopped working at retirement age. His legs continued to worsen and by 1997 he was using a walker. On examination he was again noted to be spastic and hyperreflexic, worse in the legs than the arms, but to have normal strength. He was given vitamin B12 therapy without improvement in symptoms.

By 2001 he had some trouble with his hands and his handwriting deteriorated such that he was forced to use a typewriter. By 2004 he was using a scooter for mobility outside the house. He hired an aide to help him at home. His voice changed and he had trouble managing his saliva. On examination speech was described as high pitched, strangulated, and slow. There was no focal weakness, wasting or fasciculation including in the tongue. Tone was increased in all limbs, worse in the legs. He was hyperreflexic throughout with bilateral Hoffmann and Babinski signs. EMG was repeatedly normal, Gordon et al 2 showing no evidence of denervation. In 2006, at age 76, 35 years after symptom-onset, he continued to live independently at home, but by that time the ALSFRS-R had deteriorated to 23 and FVC was 82% of predicted.

UMN-Dominant ALS with transition to ALS

A 47-year-old man first noticed a speech disorder in 1999. Several months later he became aware of emotional lability. The symptoms progressed slowly, but in 2002 his leg seemed uncoordinated and he had occasional urinary urgency. He did not have dysphagia, arm weakness, or pain in the neck or legs.

On examination in 2002, speech was slurred, but the tongue appeared normal. The pharyngeal reflex was overactive and he had a prominent jaw jerk. Muscle tone and strength were normal and there was no atrophy or fasciculation. Alternating movements were slow, more so on the right. Tendon reflexes were overactive in the arms and legs with bilateral Hoffmann and Babinski signs and clonus at the right ankle. Gait was normal. MRI of the brain in 2000 and EMG in 2002 were normal. In January 2003 MRS showed NAA/Cr ratio 2.22 on the right and 2.04 on the left (normal > 2.50). Laboratory studies, including HPS gene tests and analysis of the CSF, were normal or negative. On examination in 2003, 4 years after onset, there was mild dysarthria and some lower facial weakness. The tongue seemed slightly weak but there was no atrophy or fasciculation. Gag reflex was overactive. There was slight weakness in most muscles in the arms and hands bilaterally as well as in the right leg. The left leg had normal strength except for mild weakness of the iliopsoas. There was no atrophy or fasciculation anywhere. Reflexes were overactive with bilateral Hoffmann and Babinski signs and ankle clonus. Gait was spastic and finger and foot tapping were slow. FVC was 89% of predicted and ALSFRS-R was 39/48. Gordon et al 3 EMG in 2003 showed evidence of active and chronic denervation in the right arm and leg, thoracic paraspinal muscles and the tongue, with sparing of the left arm and the cervical and lumbosacral paraspinal muscles. Nerve conduction studies were normal. Examination in 2004 was unchanged except that fasciculations were seen in both FDI muscles as well as the right deltoid. FVC was 81% of predicted and ALSFRS-R was 32/48. His symptoms progressed. By 2008, 9 years after onset, he was able to stand only for transferring to a chair, and he spent most of his time in a wheelchair. His ALSFRS-R score was 19/48 and his FVC was 70%.

UMN-Dominant ALS A 67 year-old woman was a normal volunteer for evaluation of MRS in 1995. NAA/Cr ratio was 3.3 on the right and 2.6 on the left. In 1996 she noted hoarseness of her voice, then dysarthria and swallowing difficulties. She had no facial weakness, chewing difficulty, limb weakness, sensory loss, sphincter disturbance, or gait disorder. Examination in 1997 showed dysarthria without facial or lingual weakness, wasting, or fasciculation. There was no limb weakness, focal sensory loss, tendon reflex overactivity or asymmetry, Babinski sign, clonus, or overactive jaw jerk. EMG was normal in the left arm with mild fasciculations and fibrillations in the tongue and borderline evidence of chronic denervation in the limbs. Vastus lateralis muscle biopsy showed mild neurogenic abnormalities. Laboratory studies, including HSP gene and CSF analysis, were normal or negative. Increased MRI signal was noted in the corticospinal tracts bilaterally. Dysarthria was severe on examination in 1998. Movements of the tongue were limited and slow. There was overt atrophy of the margins of the tongue and there were fasciculations. There was no facial weakness. The uvula did not move on volition but did on reflex stimulation. There was no weakness, wasting, or fasciculation in limb muscles. Tendon reflexes were brisk but there were no Hoffmann signs. There was a left Babinski sign. Alternating movements were carried out well in the arms but slow in the legs. There was no overt emotional lability. Gordon et al 4 EMG in 1998 showed fasciculation potentials in several muscles of the left leg. There were rare positive sharp waves in the medial gastrocnemius. Motor units were of normal configuration but recruitment was diffusely mildly reduced compatible with UMN firing pattern. On examination in 2000 she was almost completely anarthric. There was bifacial weakness and almost complete inability to move the tongue. Her palate did not elevate volitionally but did have brisk reflex elevation. Tendon reflexes were overactive throughout with bilateral Hoffmann signs and left Babinski sign. The jaw jerk was brisk with clonus. Alternating movements in the arms were slow. Deltoid muscles showed full strength, but biceps were mildly weak on the right and triceps were mildly weak on the left. Wrist flexors, extensors, and finger-flexors were full strength. Finger extensors were mildly weak. There was mild proximal weakness in the legs with good distal strength. She could walk only with assistance and was extremely stiff. Sensation was intact. She reported urinary frequency without incontinence. She began having leg cramps and dysphagia, but maintained body mass with soft foods. In 2002, the ALSFRS-R score was 27/48 and FVC was 10% of predicted. She was anarthric and now had marked weakness in her arms and legs as well as facial weakness. On examination in 2004 she was anarthric, though she could move her tongue slightly. There was no obvious atrophy or fasciculation of the tongue. Glabellar and snout reflexes were present. Her left arm was non-functional and she had limited function of the right arm. She was severely spastic. Atrophy was seen only in the hands and fasciculation only in the right gastrocnemius muscle. She could stand to assist for transfers but was unable to walk. Her arms and legs were very weak. Tendon reflexes were all overactive and bilateral Hoffmann signs were elicited. Sensation was normal. ALSFRS-R score was 21/48. By 2007, 13 years after onset, she was quadriplegic and dependent on a caregiver for all activities. Her ALSFRS-R score was 14/48.