9.1.1 Clinical History – Main Complaint

A 59-year-old, right-hand-dominant man presented to the emergency department complaining that he could not move his right foot. Over the past month his right leg had become progressively weaker. He had difficulty climbing stairs and was frequently tripping over his right foot, which had resulted in more than one serious fall. During this period he felt a sensation of muscle tightness and frequent cramps in his right posterior thigh and lower leg.

In addition, the patient complained of poor memory and emotional lability. He was having difficulty remembering names of people he knew well, and had gotten lost in familiar places on several occasions. He reported irritability and frequent outbursts of anger, while his daughter noted rapid shifts from anger to tears.

9.1.2 General History

On detailed questioning the patient reported that he had been having difficulty walking for a few months. He described that his right foot would flop and smack the ground when he walked. He had presented to the emergency department 1 month prior after he tripped on a sidewalk and struck his head, leaving him unconscious for a brief period of time. He also reported a 3-year history of burning pain in both feet, at times severe, accompanied by intermittent numbness.

He denied having difficulty chewing, swallowing, speaking, or shortness of breath. He did note urinary urgency and frequency, and in fact had experienced more than one episode of urinary incontinence recently. He had no bowel difficulties.

The patient had lost approximately 45 kg in weight over the previous year, which he stated was intentional due to dietary changes. He had undergone right shoulder surgery to repair a rotator cuff injury 3 years prior. He had undergone a remote appendectomy and had been involved in a motor vehicle collision at 15 years old that resulted in multiple fractures and a shoulder injury. He was taking no medications and had no known allergies.

He was divorced and had two children. He had achieved a grade 12 education and worked as a commercial truck driver and transport coordinator. He reported drinking an average of two alcoholic beverages daily. He had stopped smoking 20 years previously. He denied any current or historical recreational drug use.

9.1.3 Family History

The patient’s mother had a history of dementia, with onset in her early 60s. His mother was 1 of 11 children, and seven of them had suffered from dementia at unknown ages. The patient himself was the third eldest in a family of eight children, and none of his siblings were known to suffer from cognitive difficulties. The patient’s children were unaffected. There was no other family history of neurological disease.

9.1.4 Examination

The patient’s general medical examination was normal. He was alert and oriented but had difficulty conveying the specifics of his recent medical history. Language was intact with normal fluency, comprehension, repetition, and naming. Cognition was assessed with the Montreal Cognitive Assessment (MoCA) screening test, on which the patient scored 20/30, consistent with mild cognitive impairment. He struggled to copy a shape and was only able to name one of three animals. The patient also struggled with serial subtractions by seven and categorical abstraction. His delayed recall was one of five words.

On cranial nerve examination the patient had full extraocular movements without nystagmus and no ptosis. Facial motor and sensation were normal. His tongue was mildly atrophic with fasciculations. He had positive glabellar tap and bilateral palmomental reflexes. He had a positive grasp reflex.

Motor examination revealed decreased bulk in the spinati muscles as well as the thighs and lower legs bilaterally. Subtle fasciculations were evident in his shoulders and arms, with profuse fasciculations in the legs bilaterally. Tone was normal in the upper extremities and increased in the lower extremities. Upper extremity power was Medical Research Council (MRC) grade 5 bilaterally. In the lower extremities he had reduced power with MRC grade 3/4+ (right/left) hip flexion, 4/4 hip abduction, 4/4 hip adduction, 3/5 knee extension, 3/5 knee flexion, 1/5 ankle dorsiflexion, and 2/5 ankle plantar flexion.

Deep tendon reflexes were 2+ in the upper extremities, 3+ at the knee, 2+ at the ankle, and symmetrical throughout. He had positive crossed adductor responses. His right plantar reflex was upgoing, while the left was downgoing.

Sensory examination was normal throughout the upper extremities. He had decreased pinprick and temperature sensation in a stocking distribution to the knees. Vibration sensation was absent and joint position sense was reduced in the right great toe, but normal on the left.

On coordination testing the patient had normal finger-to-nose and heel-to-shin tests. Gait was stable but notable for a significant right foot drop. Romberg sign was negative.

9.1.5 Special Studies

Magnetic resonance imaging (MRI) of the brain revealed nonspecific small vessel ischemic changes. Brain volume was well preserved for his age and there were no areas of focal atrophy. MRI of the spine was unremarkable. An FDG PET brain scan (Figure 9.1) revealed moderate hypometabolism in the frontal and anterior temporal lobes as well as the insular cortices and the anterior aspects of the cingulate gyri, in a pattern compatible with behavioral variant frontotemporal dementia (bvFTD).

Figure 9.1 FDG PET imaging results. The patient (left) is shown in comparison with a normal study (right). Arrows indicate (a) frontal convexity, (b) anterior cingulate gyrus, (c) frontal operculum, (d) insular cortex, and (e) anterior temporal lobe. The changes are symmetric (but only one side indicated by arrows). The findings are suggestive of frontotemporal dementia.

Electromyographic studies revealed active denervation and fasciculations in the right leg and fasciculations in the right arm. Nerve conduction studies revealed no evidence of large fiber involvement. Initial studies did not strictly meet El Escorial criteria for motor neuron disease, although taken with the clinical exam were highly suggestive.

On serology the patient had a normal CBC, electrolytes, creatinine, liver enzymes, hemoglobin A1c, and urinalysis; vitamin B12 was supratherapeutic; TSH was borderline elevated; methylmalonic acid was normal; HIV, syphilis, and lyme serology were negative; lead and aluminum levels were normal; rheumatoid factor was negative; serum and urine protein electrophoresis were normal.

Neuropsychological testing was performed. On the amyotrophic lateral sclerosis (ALS) Cognitive Behavioral Screen he scored 14/20, consistent with severe impairment relative to healthy controls. He lost points on mental addition, tracking, and monitoring, and on initiation and retrieval tasks. On verbal skills testing, he had mildly impaired categorical fluency and severely impaired verbal abstract reasoning. Visuospatial skills, and attention and working memory were all generally intact. New learning and memory was impaired with verbal material (retention of 6/16 words over five learning trials) but intact with visuospatial material. On executive skills testing, he had semantic and language-related deficits including severely impaired verbal abstract reasoning, visuomotor tracking, and moderately impaired category fluency. Collectively, his neuropsychological profile was suggestive of left hemisphere dysfunction suspicious for an emerging dementia.

Genetic testing confirmed C9orf72 hexanucleotide expansion with 30 GGGGCC repeats (normal range 2–24).

9.1.6 Diagnosis

Electrophysiological studies were highly suggestive of motor neuron disease. In the context of the clinical exam and appearance of frontal lobe dysfunction, along with confirmation of C9orf72 GGGGCC hexanucleotide repeat expansion, a diagnosis was made of ALS-FTD. The patient did not strictly meet International Consensus Criteria for probable bvFTD, given the absence of MRI findings consistent with bvFTD.¹ However, FDG PET results were strongly suggestive of the diagnosis of bvFTD and can be more sensitive in early disease. The presence of a known pathogenic genetic mutation for this phenotype provides a definitive diagnosis.

ALS-FTD was suspected when this patient first presented. The presence of upper and lower motor neuron weakness along with personality changes in a patient with a strong family history of dementia immediately raised suspicion for disease caused by autosomal dominantly inherited C9orf72 hexanucleotide repeat expansion. Roughly 1 in 10 ALS patients carry C9orf72 repeat expansion and FTD occurs in about half of these patients.² Given this frequency, C9orf72 repeat expansion should be suspected in any ALS patient with a strong family history of ALS or FTD.

9.1.7 Follow-Up

The patient’s motor function declined steadily. Six months after his initial presentation and subsequent diagnosis he began to urinate every 30 min, without sensation, and as a result he was regularly incontinent. Urodynamic studies led to a diagnosis of neurogenic overactive bladder and obstructive voiding. He had progressive loss of power along with muscle atrophy, increased fasciculations, and increased tone with spasticity. In addition to this he continued to suffer from severe burning in the lower extremity from a neuropathic pain that was long-standing and poorly responsive to treatment. Repeat electrophysiology studies 9 months after the patient first presented met El Escorial criteria for motor neuron disease.

The patient’s driver’s license was initially suspended due to concerns over cognition and motor strength. This was particularly concerning to the patient because his livelihood was based on driving. His behavior when discussing driving with his family and healthcare team was frequently aggressive and at times threatening. The patient challenged the driving test and regained his license for a brief period. He did not agree to stop driving until he had a low-speed collision with a post.

The patient’s sisters began to note that he was gambling more frequently at the racetrack and losing significant amounts of money. He was also pursuing online scams that in the past he would not have considered according to family. He was unable to pay bills, which were being covered by his daughter. He was unconcerned by his inability to manage his finances. He had poor insight into his illness and was frequently in denial. He repeatedly refused home care support despite ongoing concern from his family for his safety.

Neuropsychological testing was repeated. He scored 13/20 on the ALS Cognitive Behavioral Screen and 110/144 on the Dementia Rating Scale, placing him in the severely impaired range. The assessment indicated declines in single-word recognition, category fluency, and phonemic fluency. He had a marked decline in confrontation naming with semantic paraphasic errors evident. He exhibited executive limitations including poor abstract reasoning, slow processing speed, and diminished sensitivity to punishment associated with decision-making impairment. Simple attention and working memory were intact, as was delayed recall for visuospatial information. His language decline had features of semantic variant primary progressive aphasia.

The patient was briefly admitted to hospital 1 year after his initial presentation with failure to thrive and frequent falls at home resulting in an ankle injury. On discharge he was transferred to a long-term care facility and a declaration of incapacity was completed. Shortly after transfer he was unable to reposition himself in bed and was requiring full lift transfers due to weakness. He was suffering from depressed mood that was not responsive to antidepressant medication. Nursing staff reported multiple episodes of aggression, verbal abuse, and at least one occasion of physical abuse. His behavior was a significant stress for his family, who were frequently forced to intervene to assist long-term care staff. The patient’s family eventually decided to have him undergo stem cell treatment at an out-of-country private institution, against medical advice, resulting in no perceivable change in his condition.

9.2.1 Epidemiology and Genetics

Up to 50% of patients with ALS experience cognitive dysfunction and about 5–10% have FTD.⁴ Similarly, in one cohort study, about 15% of patients with FTD developed motor neuron dysfunction, although no population-based studies are available.⁵

Sporadic cases of FTD in association with ALS are also seen in conjunction with familial associations. The most common genetic cause of FTD-ALS is C9orf72 hexanucleotide repeat expansion.⁶ Other rare mutations noted in cases of FTD-MND include valosin-containing protein (VCP), sequestosome 1 (SQSTM1), optineurin (OPTN), and ubiquilin 2 (UBQLN2).^{7, 8} C9orf72 repeat expansion is inherited in an autosomal dominant manner. It is estimated that 56% of familial FTD-ALS and 14% of sporadic FTD-ALS carry this repeat expansion.⁹ The repeat tract length in unaffected individuals may vary between 5 and 10 and is usually <23. In patients with FTD-ALS, the tract is expanded to hundreds or thousands of repeats. Although it is unknown how many repeats are required to cause disease, the arbitrary cutoff for pathogenic repeats is set at 30, or 60 in some studies. The frequency is variable within population studies, with Caucasians reporting the highest carrier rate particularly in isolated populations such as Finland (29%).^{10, 11} Age of onset is highly variable (27–85 years) with a mean of 58 years.¹² A slight male predominance (1.23:1) has been proposed for FTD-ALS cases with C9orf72 mutations. In familial cases of FTD-ALS, a younger age of onset was noted with progression of generations suggesting genetic anticipation.¹² The penetrance is currently unknown but thought to be incomplete. The cumulative age-dependent disease penetrance for C9orf72 heterozygous patients is 0% at age 35, 50% at age 58, and almost 100% at age 80.¹⁰ The precise disease mechanism of this genetic lesion remains unknown. Three different mechanisms of disease have been proposed for the repeat expansion: loss of function of the gene, gain of protein toxicity due to expression of protein containing the expansion, and gain of RNA toxicity from the mutant RNA.¹³

9.2.2 Pathology

The phosphorylated form of TDP-43 is considered to be the underlying accumulating protein in susceptible areas in patients with FTD and ALS. In FTD, 40–50% of patients have TDP-43 inclusions whereas about 75–90% of ALS cases exhibit the same pathology.⁸ There are four different pathological subtypes identified in FTD based on morphology and characteristics of inclusions (Type A–D). C9orf72 repeat expansion cases usually express Type B TDP-43 pathology.¹⁴ A hierarchical pattern of infiltration of TDP-43 has been identified pathologically for both FTD and ALS with greatest overlap in Type B pathology. The pathology of FTD-ALS show loss of anterior horn and cranial nerve nuclei motor neurons with microglial activation in the corticospinal tracts in addition to TDP-43 deposition.¹⁵ In addition, C9orf72 cases show presence of neuronal cytoplasmic inclusions and nuclear RNA foci that stain positive for ubiquitin and p62 but not for TDP-43¹⁴ in extra motor regions such as hippocampal pyramidal neurons, and granular and molecular layers of the cerebellum.¹⁶